[Diamine oxidase as blood biomarker in rats and humans to GI tract toxicity of fluorouracil anti-cancer drugs].

Diarrhea is a side effect of a 5-fluorouracil (5-FU) anti-cancer drug-induced intestinal mucosal disorder, which sometimes becomes more severe. Blood diamine oxidase (DAO; EC1. 4. 3. 6) activity is reported to be significantly correlated with activity in the small intestinal mucosal tissue, and to be a reliable indicator of small intestinal mucosal integrity and maturity. Here, we investigated whether blood DAO activity can be a biomarker for the gastrointestinal (GI) mucosal disorder caused by 5-FU anti-cancer drugs, both in rats and humans. From results of the rat study, the degree of jejunal mucosal disorder caused by the 5-FU anti-cancer drug was well correlated with a decrease in blood DAO activity. Clinically, 12 out of 28 patients (43%) administered 5-FU anti-cancer drug suffered from diarrhea. The plasma DAO activity within one week of the onset of diarrhea significantly decreased compared with that before the administration. Furthermore, before drug administration, plasma DAO activity in patients suffering from diarrhea was higher than those in patients without diarrhea. Although DAO activity differs by the individual, it is a useful biomarker for estimating the degree of intestinal mucosal disorder, and possibly for estimating manifestations of diarrhea induced by 5-FU anti-cancer drug administration.

A phase II study of doxifluridine and docetaxel combination chemotherapy for advanced or recurrent gastric cancer.

BACKGROUND: The aim of this study was to establish the efficacy and safety of doxifluridine and docetaxel for patients with advanced or recurrent gastric cancer. METHODS: The regimen consisted of oral administration of doxifluridine 533 mg/m(2) per day on days 1-14 and an intravenous infusion of docetaxel 50 mg/m(2) on day 8. The primary endpoint was the overall response rate. The secondary endpoints were overall survival, progression-free survival, and toxicities. RESULTS: Between June 2004 and December 2006, a total of 40 eligible patients were enrolled in this study. Seven of them showed a partial response, with an overall response rate of 17.5%. The response rate was 18.8% in 32 patients with refractory tumors. The median progression-free survival time and the median overall survival time were 2.6 months and 12.7 months, respectively, in all 40 patients; and 2.6 months and 14.0 months, respectively, in the 32 patients with refractory tumors. Grade 3/4 hematological toxicity included neutropenia in 52.5%, leukocytopenia in 17.5%, and febrile neutropenia in 7.5%. Grade 3 or more nonhematological toxicities were infrequent. CONCLUSION: The combination chemotherapy of doxifluridine and docetaxel was well tolerated and relatively effective when used as a second-line chemotherapy for advanced or recurrent gastric cancer.

[A case of effective weekly paclitaxel administration for advanced gastric cancer associated with diabetes mellitus -about the control of blood glucose when dexamethasone for prophylaxis against paclitaxel-associated hypersensitivity reactions to the diabetic has been administered].

A 69-year-old woman had been treated with insulin for diabetes over the last 8 years. Distal gastrectomy (D2) was undertaken for StageIV stomach cancer. CA19-9 showed marked increases after surgery, but returned to normal after administering S-1. After 12 cycles, the treatment was discontinued due to hepatic disorders, and the clinical course was monitored. Weekly paclitaxel therapy was initiated as second-line therapy when CA19-9 rose again to 467 U/mL. Marked efficacy was noted after completion of one cycle. A total of 23 cycles were conducted. CA19-9 returned to normal, and the patient remains recurrence-free. In the treatment with paclitaxel, pre-treatment with dexamethasone (20 mg each time) is made to prevent hypersensitivity reactions. Since the total dose becomes too large in weekly treatment, however, treatment was initiated at 12 mg in our patient, and the dose was reduced stepwise to 8 mg, 4 mg and 2 mg. At the same time, the dose of insulin at bedtime and before breakfast the following morning was increased in increments of 2 units. This made it possible to maintain good control of blood glucose levels and minimize changes in HbA1c. This experience suggests that the dosage regimen needs refinements in diabetic patients such as a reduction in the dose of steroids and increases in the dose of insulin in long-term treatment.

Strangulation caused by a small bowel epiploic appendage: report of a case.

While many recent cases of colonic epiploic appendage causing acute abdomen have been reported, such appendages of the small bowel are extremely rare. We present a 59-year-old woman in whom a small bowel epiploic appendage caused volvulus. She presented with abdominal pain and vomiting in the absence of previous abdominal operations. A diagnosis of small bowel obstruction from strangulation was made. Laparotomy disclosed bloody peritoneal fluid and a closed loop of strangulated small intestine. An adherent band composed of an epiploic appendage and intestine had completely encircled a loop of jejunum, leading to obstruction. This band was released, and approximately 80 cm of gangrenous bowel was resected. Four epiploic appendages 5-6 cm in length were attached to the ileum at the mesenteric border, beginning at a point 70 cm proximal to the terminal ileum.

[A case of advanced colon cancer invading the rectum effectively treated with chemoradiation therapy before surgery].

A 56-year-old man was hospitalized for anemia with appetite loss and body weight loss. He was diagnosed as advanced sigmoid colon cancer which invaded the rectal colon (Ra) and prostate (SI, N 0, P 0, H 0, M (-), cStage IIIa). We administered neoadjuvant chemoradiotherapy for fear of non-curative resection of the sigmoid colon and rectum after colostomy was performed. He was given radiation of the whole pelvis at a total dose of 39 .6 Gy (1.8 Gy x 22 times) combined with chemotherapy using continuous intravenous 5-FU (500 mg x 22 times). Two weeks after the chemoradiation, we administered chemotherapy (FOLFOX 4). Resectable resection was confirmed on Computed Tomography. We were able to conduct a low anterior resection of sigmoid colon and rectum. Postoperative histopathological examination of the resected sigmoid colon and rectum revealed no remnant cancer tissue. Neo-adjuvant chemoradiotherapy is considered to be effective for a study of non-curative resection of rectum.

Glicentin inhibits internalization of enteric bacteria by cultured INT-407 enterocytes.

Glicentin, the main component of enteroglucagon, has trophic effects on intestinal mucosa. It may also have an inhibitory effect on extraintestinal invasion of enteric bacteria. We have established an in vitro bioassay system for determining the effects of recombinant human glicentin on bacterial internalization by confluent enterocytes. An INT-407 cell line was serum-deprived for 2 days and was then treated on transwell filters for 24 h with a medium containing one of the following: glicentin 100 ng-1 microg/ml, glucagons-like peptide-2 (GLP-2) 1 microg/ml, 10% fetal bovine serum (FCS), or without any growth factors. Pure cultures of Salmonella enteritidis, Escherichia coli, and Enterococcus faecalis were introduced to the upper chambers of the filter units. Following 2 h of incubation the numbers of bacteria in the lower chambers were measured. Pretreatment of enterocytes with glicentin inhibited bacterial internalization compared to untreated or GLP-2 enterocytes. Glicentin was associated with inhibition of enterocyte internalization of enteric bacteria by a mechanism that might be related to the integrity of the enterocyte adhesive junctions and tight junctions and to the production of sIgA. Glicentin seems to have a function as a barrier-sustaining agent that inhibits extraintestinal invasion of enteric bacteria.

[Mycobacterium fortuitum infection caused by the organism in subcutaneous abscess mediated by central venous catheter].

A 49-year-old woman with a Mycobacterium fortuitum bloodstream infection, who has been managed with central venous (CV) catheterization for two years, was reported. She had undergone rectectomy for rectal cancer and gastectomy for stomach cancer at the ages of 36 and 42, respectively. Also, she had undergone adhesiotomy for four times for postoperative ileus at the ages between 44 and 47. She was admitted to our hospital because of fever (38.4 degrees C) with chill and fatigue, and a subcutaneous abscess at the right infraclavicular region located at the insertion site of the CV catheter (Hickman catheter). After the catheter was removed, the subcutaneous abscess was incised and a Penrose drain tube was inserted. M. fortuitum was detected after three days of blood culture and on the blood agar medium inoculated with purulent discharge from the drainage tube. After receiving these treatments, she was discharged from the hospital one month later. The isolates from these blood and purulent discharge specimens were identical on pulsed-field gel electrophoresis. Based on these findings, we concluded that the M. fortuitum bloodstream infection in this case might be caused by the organism in the subcutaneous abscess mediated by the CV catheter.

Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor.

Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1, G --> A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5' ss in the mutated allele generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis of GISTs in NF1 patients is different from that in non-NF1 patients.

[Thymidylate synthase and dihydropyrimidine dehydrogenase expression and histological effects of preoperative UFT in gastric cancer patients].

UNLABELLED: During DNA synthesis in tumors, fluoropyrimidine anticancer agents target thymidylate synthase (TS) that catalyze the synthesis of dTMP from dUMP and are metabolized by dihydropyrimidine dehydrogenase (DPD). We administered UFT to patients with gastric cancer preoperatively to prevent cancers from advancing while they await surgery or down staging. PATIENTS AND METHODS: We administered UFT to 24 gastric cancer patients at 360 mg/m(2)/day for longer than 3 weeks as a preoperative chemotherapy. TS and DPD expression in the tumor were measured by immunohistochemistry staining before and after (during surgery) chemotherapy and compared with the results of histological assessment. RESULTS: TS and DPD expression decreased significantly after UFT administration (p<0.05). Histological assessment showed Grade 1 b or 2 in 11 of 24 patients (46%). Eight of 15 patients with high DPD (53.3%) exhibited Grade 1 b or 2. CONCLUSIONS: Histological assessment revealed the efficacy of UFT, through a DPD-inhibitory fluoropyrimidine (DIF) effect, in patients with high DPD. This suggests that preoperative administration of UFT can be a useful clinical measure.

[Case study--an elderly patient with Stage IV advanced gastric cancer achieved good performance status (PS) without subjective symptoms for more than two years by chemotherapy].

An 83-year-old male with Stage IV gastric cancer of performance status 1 (PS 1) was treated with fluoropyrimidine (TS-1) since January 2003 in our department. As the patient exhibited decreased renal function due to his age, we set the basic dose at 80% of the recommended dose of 80 mg/body/week. We administered 11 four-week cycles, each with a two-week drug-free washout period, and six two-week cycles, each with a two-week drug free washout period. The first cycle of chemotherapy ameliorated the subjective symptoms; the level of a tumor marker then returned to normal, and the ascites disappeared. The patient's condition was maintained at a favorable PS level without any subjective symptoms for approximately 20 months. In late September 2004, however, an exacerbation of the primary foci was confirmed by routine endoscopic examination. As second-line chemotherapy, we initiated weekly administration of paclitaxel (PTX). Due to the patient's age and high PS level (PS 2) at the time of intervention, we utilized a reduced dose of 70 mg/body/dose. After a short premedication period, the patient was administered PTX intravenously for one hour once a week for three weeks, then given a one-week drug-free washout period (one cycle). After the first cycle of PTX administration, all subjective symptoms disappeared, the PS level returned to zero,and the patient was discharged. In total, four cycles of the PTX regimen were given. Throughout the treatment period, we did not observe any significant adverse events (grade 2 or higher). Treatment achieved a favorable PS level. To design an effective chemotherapy regimen for elderly patients, it is important to establish an effective dose and dosing method based on the patient's chronologic age and a thorough evaluation of the patient's systemic conditions, including the PS level.

Diamine oxidase, a plasma biomarker in rats to GI tract toxicity of oral fluorouracil anti-cancer drugs.

Diamine oxidase (DAO; EC 1.4.3.6), which catabolizes a variety of substrates including histamine and diamines, is the degradative enzyme of the catabolic pathway of polyamines found in high activity in the mature upper villus cells of the rat intestinal mucosa [Luk, G.D., Bayless, T.M., Baylin, S.B., 1983. Plasma post-heparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat. J. Clin. Invest. 71, 1308-1315; Wolvekamp, M.C.J., de Bruin, R.W.F., 1994. Diamine oxidase: an overview of historical, biochemical and functional aspects. Dig. Dis. 12, 2-14]. Rats were given 1-week repeated oral administration of anti-cancer drugs S-1, containing FT+CDHP+Oxo, and FCD, containing FT+CDHP, and the ameliorating effect of Oxo on the rat gastrointestinal (GI) tract toxicity from 5-FU was evaluated by measuring plasma DAO activity which is related to the enzyme located in the rat intestinal mucosa. Plasma DAO activity in the FCD-treated group was significantly less than that in the S-1-treated group while the jejunal mucosal area in the FCD group was significantly smaller than that in the S-1 group. In addition the histopathological findings in the FCD group showed villus atrophy in the jejunal mucosa which was not observed in the S-1 group. The degree of these findings correlated with the plasma DAO levels. Therefore, the protective effect of Oxo on 5-FU-induced GI tract toxicity was clarified by measuring plasma DAO activity in rats. In summary, DAO is a very sensitive plasma biomarker and will be useful for the quantitative evaluation of the small intestinal mucosal lesions induced by the anti-cancer drug, 5-FU, in rats.

Prediction of pancreatic fistula by amylase levels of drainage fluid on the first day after pancreatectomy.

BACKGROUND/AIMS: We investigated whether it would be useful to monitor amylase levels of drainage fluid after pancreatic surgery for prediction of pancreatic fistula. METHODOLOGY: Twenty-six cases in which amylase levels of drainage fluid were determined after pancreatic surgery, were divided into 14 cases who did not develop pancreatic fistula and 12 cases who developed pancreatic fistula. Changes in amylase levels of sera and urine as well as drainage fluid were monitored. RESULTS: Amylase levels of drainage fluid were significantly higher in cases with pancreatic fistula than in cases without pancreatic fistula on the first postoperative day, but those levels in both groups decreased until the 7th postoperative day without significant difference. However, those levels in cases with pancreatic fistula significantly increased from the 9th postoperative day whereas the levels in cases without pancreatic fistula further decreased. There was no significant difference in amylase levels of sera or urine. CONCLUSIONS: Amylase levels of drainage fluid on the first postoperative day may be useful to predict development of pancreatic fistula and to plan appropriate management.

[Complete remission of esophageal undifferentiated carcinoma with nedaplatin and 5-FU chemotherapy and endoesophageal brachytherapy].

The patient was a 74-year-old female. Type 1 undifferentiated carcinoma (non-small cell type) was detected in the middle of the thoracic esophagus in August 1999. Although the lesion was diagnosed as T2, N0, and Stage II, the patient was judged to be a poor risk, inoperable case because of a complex past history of renal and respiratory dysfunctions, and dysbasia. Intravenous administration of nedaplatin at 15.8 mg/m2 and 5-FU 590.6 mg/m2 were carried out for 5 consecutive days as chemotherapy. The second cycle of chemotherapy was performed with nedaplatin reduced to 11.8 mg/m2 on the basis of the adverse reactions observed after the first cycle, and PR was attained. As for radiotherapy, additional extracorporeal irradiation was judged to be too dangerous from her history, so endoesophageal brachytherapy alone was added, and CR was obtained. The patient has maintained a CR for more than 2 years after discharge. In this poor risk case with a highly malignant undifferentiated carcinoma, an "individualization strategy" was effective.

Hepatocellular carcinoma in a patient with acromegaly and high serum levels of insulin-like growth factor I: report of a case.

A 64-year-old woman with high serum levels of growth hormone, insulin-like growth factor-I (IGF-I), and alpha-fetoprotein resulting from partially treated acromegaly was found to have a tumor under the left diaphragm. The patient also had a history of type C viral hepatitis. Laparotomy revealed that the tumor was fixed to the diaphragm and connected to the liver and spleen. The tumor was excised with partial resection of the diaphragm, liver, and spleen, and a diagnosis of left-sided pedunculated hepatocellular carcinoma (HCC) was made. Further examination showed a higher level of IGF-I receptor mRNA in the tumor than in the normal liver parenchyma. We believe it is likely that the high serum levels of IGF-I may have played a role in the development of the pedunculated HCC in this patient.