Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

A novel triple secured technique for pancreatic reconstruction following pancreaticoduodenectomy for a soft pancreas.

BACKGROUND/AIMS: Soft pancreases are susceptible to developing pancreatic fistula following pancreaticoduodenectomy. To reduce the incidence of pancreatic fistula after pancreaticoduodenectomy in patients with a soft pancreas, we developed a triple secured technique. In this study, we describe the details of this technique and also report on the postoperative outcomes. METHODOLOGY: The triple secured technique employed an ultrasonic dissector for pancreatic transection with skeletonizing and ligating of the small pancreatic branch ducts, duct-invagination or duct-to-mucosa anastomosis for main pancreatic duct management, and, finally, four large stitches between the pancreatic stump parenchyma and the jejunal seromuscular layer to prevent minor pancreatic leakage. A total of 28 consecutive patients with a soft pancreas who underwent pancreaticoduodenectomy using our technique were included in this study. RESULTS: Postopetrative complications occurred in 16 patients. Grade B pancreatic fistula developed in 6 patients. However, no grade C pancreatic fistula occurred in this series. Neither any reoperation nor in-hospital mortality was observed in this series. CONCLUSIONS: Our triple secured technique after pancreaticoduodenectomy was feasible and safe, with an acceptable rate of grade B pancreatic fistula and no grade C pancreatic fistula for patients with a soft pancreas.

Multicenter phase II trial of combination chemotherapy with weekly paclitaxel and 5-fluorouracil for the treatment of advanced or recurrent gastric carcinoma.

The aim of this study was to investigate the efficacy and safety of combination chemotherapy with weekly paclitaxel and 5-fluorouracil (5-FU) as first-line treatment in patients with advanced or recurrent gastric carcinoma. A total of 65 patients were treated with the following regimen, administered every 28 days; 5-FU 600 mg/m2 by 24-hour continuous infusion from days 1 through 5, and weekly paclitaxel 80 mg/m2 by 3-hour intravenous infusion on days 8, 14, and 21. A total of 272 cycles were conducted with a median of 4 (2-13) cycles per case. Out of 57 patients with measurable disease by RECIST criteria, there were 2 complete responses (3.5%), 20 partial responses (35.1%) and 25 cases with stable disease (43.9%). The overall response rate was 38.6% (95%CI: 26.0-51.2%). The median survival time and 1-year survival rates were 329 days and 47.4%, respectively. Both hematologic and non-hematologic toxicities were well tolerated.

cDNA structure of an insulin-related peptide in the Pacific oyster and seasonal changes in the gene expression.

Insulin-related peptide cDNA was characterized in the Pacific oyster Crassostrea gigas. It was determined that three transcripts with differing lengths of 3'-untranslated region (3'-UTR) were expressed in the visceral ganglia. The insulin-related peptide cDNA contained a number of AUUUA motifs that were typical of adenylate/uridylate-rich elements in the 3'-UTR. The deduced preprohormone was a polypeptide of 161 residues and showed a conformation typical of preprohormones of the insulin superfamily, which included conserved amino acids necessary to adopt the globular insulin structure. The expression of the three different transcripts was variable throughout the year, with the highest expression observed in March and lower expression in November and July. The expression of the shortest mRNA in March was about tenfold higher than in July, while the expression of the longest transcript varied approximately twofold during the year. The accumulation of glycogen in the soft body rapidly increased in October and November, and robust body growth and gametogenetic development occurred in March to May. The period of the highest expression of the oyster insulin-related peptide gene corresponded to the onset of body growth and gametogenetic development, but did not overlap with the period of glycogen accumulation. This is the first report that fully details the structure and expression of the insulin-related peptide gene in bivalves.

Use of multislice helical computed tomography cholangiography in the diagnosis of biliary disease.

A recent advance in computed tomography (CT) technology, multislice helical CT, has enabled production of clearer three-dimensional (3D) images and has drawn interest. We report the usefulness of CT cholangiography using a multislice helical CT scanner for the diagnosis and preoperative imaging of the biliary duct in a case of peculiarly shaped gallbladder with cholecystitis. A 34-year-old woman admitted to our hospital presented with chronic hypochondralgia. A CT scan showed that the gallbladder was normal without wall thickening or stones. However, there appeared to be a tumor, containing a stone approximately 1 cm in diameter, attached under the gallbladder in front of the right kidney and extending up to its lower level. Magnetic resonance cholangiography also depicted a normal gallbladder without wall thickening or stones. Hence, gallbladder stones were not diagnosed by previously the mentioned investigations. In contrast, a 3D image produced by multislice helical CT cholangiography was very clear. From the bottom of the gallbladder, a narrow canal continued to a stone. We diagnosed that the wall of the lower part of the long gallbladder had become thick and elongated because of chronic cholecystitis caused by a gallbladder stone, and laparoscopic cholecystectomy was performed. Macroscopically, the resected gallbladder showed an extremely thickened wall from the lower body to the fundus, in which a stone was located in the center. Multislice helical CT cholangiography has the potential to become one of the most significant examinations for diagnosis and anatomical analysis of biliary disease prior to laparoscopic cholecystectomy.

Retrohepatic vena cava replacement of hepatic malignancies without using total hepatic vascular exclusion or extracorporeal bypass.

Total hepatic vascular exclusion and venovenous bypass are frequently used surgical procedures when concomitant resection of the inferior vena cava is required during surgery of liver cancer involving the retrohepatic inferior vena cava close to the hepatic veins. However, the duration of total hepatic vascular exclusion is limited due to the risk of hepatic ischemia. Three patients presented with severely compressed inferior vena cava and/or hepatic veins due to liver cancer. The surgical procedure involved initial taping of the inferior vena cava just below the hepatic veins by extrahepatic division and taping of the hepatic veins. After taping the inferior vena cava, hepatectomy with caval resection was performed by simply clamping the retrohepatic inferior vena cava, without the need for total hepatic vascular exclusion or venovenous bypass. In all patients the retrohepatic inferior vena cava were safely replaced with a prosthetic graft under stable hemodynamics. Duration of the inferior vena cava clamping was 31, 66, 75 minutes, respectively. No graft-related complications occurred, but 2 of the 3 patients showed temporal renal dysfunction associated with renal congestion postoperatively. The surgical procedure described herein is effective for the treatment of retrohepatic inferior vena cava in some patients. However, when the case is complicated by chronic nephropathy or simultaneous nephrectomy is required, venovenous bypass should be performed.

Long-term survival after resection for small cell carcinoma of the esophagus.

We describe the rare case of a patient with esophageal small cell carcinoma who was completely cured. A 77-year-old man had small cell carcinoma of the esophagus with extensive lymph node metastases. Treatment comprised a subtotal esophagectomy and extended lymph node dissection. He has survived for more than 7 years with no evidence of recurrent disease. We suggest that radical operations should be considered for future patients if curative resection can be expected.

Extent of pathologic invasion of the inferior vena cava in resected liver cancer compared with possible caval invasion diagnosed by preoperative images.

The extent of cancerous invasion of the inferior vena cava (IVC) determined from resected liver cancer was examined pathologically. Ten patients presenting with liver cancer (metastatic liver cancer, five patients; hepatocellular carcinoma, three; and cholangiocellular carcinoma, two) were diagnosed with positive IVC invasion using preoperative imaging techniques of extracorporeal ultrasonography, computed tomography, magnetic resonance imaging, and vena cavography. The diagnostic criterion for positive IVC invasion by preoperative imaging was longitudinal IVC compression measuring over 50 mm, or transverse IVC compression extending to more than half the circumference of the IVC, or the presence of lesions protruding into the IVC lumen, or the presence of developed collateral veins. All patients underwent combined resection of the IVC. However, pathology results revealed that four of the ten patients had no cancerous invasion of the IVC, and that the extent of invasion along both the longitudinal and transverse axes of the IVC was much smaller than the compression shown by imaging results. We believe that detailed preoperative assessment, using a more precise imaging technique, as well as further intraoperative examination, is required to predict the full pathological extent of cancerous invasion of the IVC.

[Outcomes of home anti-cancer chemotherapy--estimation of hepatic arterial infusion chemotherapy for patients with multiple liver metastases].

A total of 18 patients (13: colon cancer, 5: gastric cancer) with multiple liver metastases (H3) underwent hepatic arterial infusion chemotherapy (HAI) using an implanted arterial port with portable syringe pumps in our outpatient clinic. Clinical perspective: overall response rate was 22.2% (CR: 1 case, PR: 3 cases (1 case: hepatectomy after HAI), NC: 12 cases, PD: 2 cases), however, 7 of 12 cases of NC were long NC (more than 6 months). No major complications with HAI were experienced. Patient Perspective: After HAI in our outpatient clinic, the 50% survival was 341 days, 50% hospital free days were 319 days and home stay rate was 92.9%. Societal Perspective: cost and hospital stay days were significantly reduced. Home anti-cancer chemotherapy using HAI for gastrointestinal cancer patients with multiple liver metastases was safe and efficient from the viewpoint of medical outcomes.

Recurrent mesenteric desmoid tumors with multiple peritoneal dissemination: a case report and review of desmoid in Japan.

We report, herein, on the first case of a mesenteric desmoid tumor with multiple peritoneal dissemination. A 73 year-old Japanese woman, who had a history of uterine cancer that was treated with hysterectomy followed by a high dose of irradiation 25 years ago, had an unknown stenosis of the sigmoid colon, which was treated with partial resection of the stenosed colon 6 years ago, and then resulted in multiple small bowel obstructions due to the recurrence of mesenteric desmoids. The clinical behavior of this tumor is considered to be unpredictable. We emphasize that mesenteric desmoid tumors should be considered as one of the causes of stenosis of the colon and small bowel, and patients should receive careful follow-up after unknown stenosis.

Increase in portal blood interleukin-6 soon after the commencement of digestive surgery.

To determine whether cytokines produced in the operative field during digestive surgery selectively spill over into the portal blood, the changes in interleukin-6 (IL-6) levels in portal and peripheral venous blood were assayed at several points in time from the commencement of surgery until 14 days later, in 11 patients. Similar changes in the IL-6 levels were observed in the portal and peripheral blood samples; however, the IL-6 levels in the portal blood reached a maximum 6-12h after the commencement of surgery, being earlier than in the peripheral venous blood. In fact, between 3 and 12h after the commencement of surgery, the IL-6 levels were higher in the portal blood by 33-81 pg/ml. By 24h or more after the commencement of surgery, the IL-6 levels did not differ significantly in the two types of blood samples. Moreover, the C-reactive protein levels 2 days after surgery were even more closely correlated to the maximum IL-6 levels in the portal blood than to those in the peripheral venous blood. These results suggest that IL-6 produced during intra-abdominal digestive surgery initially enters the portal blood, being trapped by IL-6 receptors in the liver, where it may regulate the synthesis of acute-phase proteins as a hepatocyte-stimulating factor.

Transfected mutant p53 gene increases X-ray-induced cell killing and mutation in human fibroblasts immortalized with 4-nitroquinoline 1-oxide but does not induce neoplastic transformation of the cells.

We introduced the mutant p53 gene (codon 273Arg-His) into human fibroblasts (SUSM-I cells) previously immortalized with 4-nitroquinoline I-oxide (4NQO) and obtained 2 clonal cell lines (SUSM-i/p53-1 and SUSM-1/p53-6) expressing the mutant p53. Since the genetic background of SUSM-1/p53 is the same as that of SUSM-1 except for the presence of the mutant p53, we expected to obtain more information on the mechanisms of p53 functions without the influence of other genetic differences by comparing cellular characteristics of both cell lines. SUSM-1/p53 cells became about twice as sensitive to the cytotoxic effects of X-rays as their parent SUSM-1 cells. Mutation frequency was determined by the appearance of hypoxanthine guanine phosphoribosyl transferase deficient (6-thioguanine resistant) cells. As a result, the mutation frequency of SUSM-1/p53 cells was about 5 times that of SUSM-1 cells transfected with or without the vector plasmid alone. Furthermore, when the SUSM-1/p53 cells were exposed to X-rays, the mutation frequency increased to about twice that of the non-irradiated SUSM-1/p53 cells. However, SUSM-1/p53 cells showed neither anchorage-independent growth in soft agar nor tumorigenicity in nude mice. These results indicate that the mutant p53 gene itself, which generally works in a dominant-negative way on cellular carcinogenesis, is not sufficient for neoplastic transformation of immortalized human cells, and that additional genetic change(s) may be necessary for transformation.

Human fibroblasts (KMST-6/RAS line) transformed with 60Co gamma-rays and c-Ha-ras oncogene constitutively produce a large amount of human granulocyte-colony stimulating factor (G-CSF).

Human fibroblasts (KMST-6/RAS) transformed with 60Co gamma-rays and the Ha-ras oncogene formed tumors in nude mice. These mice showed splenomegaly and an increase in granulocytes in the peripheral blood. There was a direct correlation between tumor size and spleen size. Histologically, prominent proliferation of granulocytes was observed in the enlarged spleen. These findings indicated that KMST-6/RAS cells might have been producing granulocyte colony-stimulating factor (G-CSF) in the nude mice. In fact, in vitro studies demonstrated that the cells produced G-CSF in the culture medium and that production of G-CSF was greater during the logarithmic growth than during the stationary phase. Nearly equal amounts of G-CSF were produced by cells grown in serum-free or 10% serum-supplemented medium. Neither expression of the ras oncogene nor the tumorigenicity of cells correlated with the production of G-CSF. G-CSF production in KMST-6/RAS cells was significantly stimulated by butyrate, but not by dexamethasone or 5-azacytidine.

[A case of inflammatory breast cancer well treated with intraarterial infusion chemotherapy-- evaluation of therapy by contact thermography].

A case of inflammatory breast cancer, for which an intra-arterial infusion chemotherapy was reported that it was effective. A 63 year-old woman was admitted with the complaint of left breast mass and reddish skin. Clinically it was diagnosed to be inflammatory breast cancer and was treated with an intra-arterial infusion. Contact thermography was employed for the efficacy of the treatment. Three weeks after the chemotherapy the temperature of the tumor site was decreased with a reduction of the tumor size. But, the opposite symptoms appeared before the tum or size increased. Contact thermography seemed to be useful for an evaluation of the preoperative chemotherapy for inflammatory breast cancer.

[Rapid assay of hyaluronic acid in serum].

A method for measurement of hyaluronic acid (HA) level in serum was developed based on using "hyaluronic acid binding protein" (HABP)-coated polystyrene beads. After the beads and test serum being mixed, the mixture was incubated together with reaction buffer for 2 hours, and then the beads were washed. Subsequently, biotinylated HABP was added to the washed beads and incubated for 1 hour. Then peroxidase-conjugated avidin was added to the mixture and incubated again for 1 hour. After the beads being washed, a substrate solution was added to the washed beads and left for 1 hour. Then the reaction was stopped by adding 2N-H2SO4. The absorbance at 492 nm was recorded. The analytical range of HA in serum by this method was found to be between 10-800 micrograms/l, and the precision of the HA assay (CV%) was between 3.0-8.4 in the "with-in" assay (n = 10), and 4.8-8.9 in the "between" assay (n = 5). The analytical recovery of HA assay was between 92-115%. In this study, the results in screening of the serum HA level in RA patients (n = 107), OA patients (n = 16) and healthy subjects (n = 30) showed that the HA level of RA patients was demonstrated significantly higher than that of healthy subjects and OA patients.

[Gastric cancer presenting fine stippled calcification in radiography: a case report and a review of the Japanese literature].

A case of calcified gastric cancer is reported, with a review of the Japanese literature with special reference to the genesis of calcification. A male patient, 51 years of age, given a partial gastrectomy for an advanced gastric cancer 5 years earlier, presented general malaise. Plain X-rays revealed fine, stippled calcifications widely distributed in the upper abdomen. Additionally, computed tomography revealed a wide expanse of high density shadows with CT numbers of calcifications. On laparotomy, a histologic examination of a specimen taken for biopsy from part of the metastatic liver tumor led to a diagnosis of a mucinous adenocarcinoma showing identical histologic features of the previously resected gastric cancer, this diagnose then confirmed by Kossa's staining of fine calcified deposits in the tumor parenchyma.