Phase I/II study of irinotecan and UFT for advanced or metastatic colorectal cancer.

UNLABELLED: The aim of this study was to determine the recommended dose of irinotecan in combination with the fixed dose of oral UFT as first-line therapy in patients with advanced or recurrent colorectal cancer, and to evaluate the response rate and overall survival as a phase II study. PATIENTS AND METHODS: Thirteen patients were recruited into a phase I trial. Four doses of irinotecan ranging from 60 to 150 mg/m2/day were administered intravenously on day 1 and day 16 in combination with UFT given orally from day 2 to day 15. In a phase II study, 53 patients received at least one cycle of this therapy. RESULTS: The recommended dose of this combination was determined as irinotecan 120 mg/m2/day and UFT 400 mg/m2/day. Dose-limiting toxicities were neutropenia and prolonged leucopenia. On an intent-to-treat analysis, the response rate in the phase II study was 24.5% (95% confidence interval 13.8% to 38.2%). The median overall survival time was 20.3 months (95% confidence interval, 15.0-22.8 months). Out of 20 patients with stable disease, 17 who received more than 4 cycles of the regimen lived longer than the other 3 patients who received fewer than 3 cycles (p = 0.0353). Hematological adverse events were mainly grade 3/4 neutropenia observed in 6 out of 53 patients. Grade 3 non-hematological toxicities, such as diarrhea, anorexia, nausea/vomiting and alopecia were observed in 6 patients. CONCLUSION: Irinotecan combined with oral UFT was effective and well-tolerated. This regimen may be considered as a first-line therapy for advanced or metastatic colorectal cancer and may result in fairly long survival, even for patients with stable disease.

Role of intraoperative enteroscopy for surgical decision making with Crohn's disease.

BACKGROUND: This study aimed to assess the role of intraoperative enteroscopy (IOE) in determining surgical treatment. METHODS: The IOE procedure was performed for 30 patients with Crohn's disease. The degree of stricture and the presence of active ulcer were examined. Preoperative diagnoses and intraoperative findings obtained by inspection and palpation were noted and compared with the IOE findings. RESULTS: Of the 78 intestinal strictures observed by IOE (42%), 33 were not found by preoperative examination. Of the 45 strictures confirmed by IOE to be severe (<15 mm in diameter), 8 were judged to be mild (15-25 mm in diameter) or were not even identified by intraoperative inspection and palpation. Active ulcer was found at 12 of 33 mild strictures, and all 12 strictures were surgically corrected. Of 11 severe strictures detected by IOE at previous surgical sites, 9 were found preoperatively, and 4 were judged to be mild on the basis of inspection and palpation. Stricture was found at the ileocecal valve by IOE in seven patients, but was not diagnosed preoperatively in two of these patients. CONCLUSION: Intraoperative enteroscopy provides useful information regarding the status of the lumen in patients with Crohn's disease.

Recovery of gastrointestinal tract motility and myoelectric activity change after abdominal surgery.

OBJECTIVE: To investigate the relationship between fedstate gastrointestinal tract (GI) function and upper GI myoelectric changes seen after abdominal surgery. DESIGN: Twenty-one adult female mongrel dogs underwent either an open cholecystectomy, a laparoscopic cholecystectomy alone, or a laparoscopic cholecystectomy with peritoneal injury (n = 7 for each group). Bipolar recording electrodes were placed on the antrum and 3 sites of the proximal small intestine to record fasting myoelectric data each morning postoperatively. Solid-phase, technetium Tc 99m gastric emptying studies were performed on postoperative days 1 and 2. Radiopaque markers were ingested just before operation, and the excreted markers were counted using x-ray films of the feces. MAIN OUTCOME MEASURES: Postoperative fasting GI myoelectric activity, gastric emptying, and intestinal transit time. RESULTS: Migrating motor complexes (MMCs) in the small intestine were observed in 33.3% and 75.0% of the dogs on postoperative days 1 and 2, respectively. Gastric dysrhythmias were observed in 23.8% and 45.0% of the dogs on postoperative days 1 and 2, respectively. No relationship between type of surgery and the presence of MMCs or gastric dysrhythmias was noted. Gastric emptying was delayed on postoperative day 1 and was unrelated to the presence of MMCs. Transit time was not significantly delayed in dogs without MMCs on postoperative day 1 compared with that in dogs with MMCs on that day. The presence of gastric dysrhythmias did not affect transit time studies. CONCLUSION: Fasting GI myoelectric activity, including the return of MMCs and the presence of gastric dysrhythmias, does not accurately predict fed-state gastrointestinal GI function following abdominal surgery.

Comparison of blood flow assessment between laser Doppler velocimetry and the hydrogen gas clearance method in ischemic intestine in dogs.

Blood flow of the colon and the ileum was measured before and after intestinal devascularization by laser Doppler velocimetry and the hydrogen gas clearance technique in 10 dogs in order to evaluate the clinical usefulness of laser Doppler velocimetry. The submucosal blood flow of the colon and the ileum measured by the hydrogen gas clearance method was significantly decreased, as was the subserosal blood flow of both sites measured by laser Doppler velocimetry. There was a linear relationship between the flow values using the two methods both in the colon (r = 0.7192, p less than 0.001) and in the ileum (r = 0.7646, p less than 0.001). These data suggested laser Doppler velocimetry may be a useful method to assess the degree of intestinal ischemia because of its noninvasiveness and good correlation with submucosal blood flow by the hydrogen gas clearance technique.

Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice.

BACKGROUND AND AIMS: Imbalance between pro- and anti-inflammatory cytokines produced by intestinal T cells induces inflammatory bowel diseases (IBD). However, the importance of regulation of cytokine signalling in IBD has not been fully clarified. We have demonstrated that suppressor of cytokine signalling 1 (SOCS1) is expressed in inflamed tissues in an experimental colitis model. In the present study, we investigated the role of SOCS1 in colitis models to clarify the mechanism of IBD development. METHODS: Intestinal T cells in transgenic mice expressing high levels of SOCS1 in lymphocytes (SOCS1Tg mice) were characterised by flow cytometric analysis and cytokine production from intestinal T cells was determined by ELISA. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis was induced in SOCS1Tg mice and severity was compared with control littermates by measurement of survival rates. Intracellular signalling was assessed by western blotting analysis. RESULTS: SOCS1Tg mice developed colitis spontaneously with age. Young SOCS1Tg mice less than 15 weeks of age, before the onset of colitis, were susceptible to TNBS induced colitis. Intestinal T cells of SOCS1Tg mice showed increased interferon gamma and tumour necrosis factor alpha production and decreased transforming growth factor beta production. Expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a negative regulator of T cell activation, in SOCS1Tg mice was severely impaired at the protein level although mRNA levels of CTLA-4 in SOCS1Tg mice were comparable with those in control mice. CONCLUSIONS: Our data suggest that SOCS1 plays an important role in the regulation of colitis by controlling intestinal T cell activation mediated through CTLA-4 expression.

Morphology following proctocolectomy in dogs: effect of introduction of a 'neocolon' using an interposed jejunal segment.

Intestinal mucosal morphology was studied in dogs given a new reconstruction procedure following proctocolectomy in which a jejunal segment was interposed between the terminal ileum and the anus to function as a 'neocolon'. Chronic inflammatory cell infiltration, villous atrophy, and fibrosis of the lamina propria were sought in three different intestinal sites and assigned a severity score. Twenty-four weeks after proctocolectomy, villous atrophy and fibrosis of the lamina propria were noted both in the interposed jejunum (neocolon) (p < 0.05, p < 0.01, respectively) and the terminal ileum (p < 0.05, p < 0.05, respectively). Similar changes were also observed in the proximal jejunum, but a significant difference compared to the preoperative time was not seen. Fibrosis of the lamina propria in the interposed jejunum tended to be more advanced than that in the other two sites. A statistical difference in severity was obtained between the interposed jejunum and the proximal jejunum (p < 0.05). Chronic inflammatory cell infiltration was similar in all sites examined. No obvious evidence of acute inflammation was found at any site examined. These data suggest that chronic morphologic changes inevitably occur at any site in the remaining intestine after proctocolectomy and that an interposed jejunal segment is most severely affected. The new interposition procedure may be effective in reducing the morphologic changes in the terminal ileum because of its proximal displacement.

Gastric myoelectric activity changes following open abdominal surgery in humans.

We examined the postoperative changes in fasting gastric myoelectric activity in 11 patients undergoing nongastric surgery (colon surgery) via celiotomy. Recordings were performed on postoperative days (POD) 1, 2, 3, 5, and 7+ (7-35) for 1-1.5 hr after overnight fasting. Patients had placement of bipolar seromuscular recording electrodes on the proximal (N = 9) and distal (N = 11) antrum at the time of surgery. Data were analyzed visually and analysis of variance or tests of proportion were used for statistical analysis. Although there was a trend of decreasing slow wave frequency from POD 1 to 7+ in the proximal and distal antrum, no significant differences were observed in slow wave amplitude or in the percentage of slow waves with spike activity between postoperative day. In a few of the patients, several types of gastric dysrhythmias were infrequently observed. We conclude that certain parameters of fasting gastric myoelectric activity do not change sufficiently following open abdominal surgery to adequately reflect clinical recovery from postoperative ileus.

Recovery of gastrointestinal motility following open versus laparoscopic colon resection in dogs.

The recovery of gastrointestinal motility was compared in dogs undergoing either laparoscopic or open sigmoidectomy. During surgery, bipolar recording electrodes were placed on the proximal and distal antrum, mid- and distal colon, and the rectum. Fasting myoelectric data were recorded postoperatively. Scintigraphic gastric emptying studies employing a solid test meal were performed before and after [postoperative day (POD) 2] operation. Ten radiopaque markers were given just before operation and retained markers were counted daily by abdominal x-ray. Gastric emptying on POD 2 was significantly delayed in the open group at 120 min compared with preoperative studies for the open group and compared with the laparoscopic group on POD 2 (P < 0.05 and P < 0.01, respectively). A significant difference in the number of retained markers was observed between the groups on POD 4 (P < 0.05). There were no significant differences in slow-wave frequency, presence of dysrhythmias in the proximal and distal antrum, or presence of either discrete or continuous electrical response activity in the colon and rectum between groups on any days. We conclude that using a laparoscopic approach results in more rapid recovery of fed-state gastrointestinal motility following colon resection. These data also suggest that myoelectric activity alone is not a sensitive enough parameter to detect these differences in recovery in this animal model.

A simplified defaecographic procedure for the assessment of faecal incontinence or obstructed defaecation.

OBJECTIVE: Various types of defaecography have been reported for research purposes. A simplified method for clinical use has not been devised for the assessment of disordered defaecation. The aim of this study was to describe a simplified procedure of defaecography and evaluate its usefulness in the diagnosis of faecal incontinence or obstructed defaecation. PATIENTS AND METHODS: Anorectal manometry and simplified defaecography were performed in 82 consecutive patients. The procedure of defaecography consisted of instillation into the rectum with a 100% weight per volume of barium in the sitting position through a Foley catheter with an inflated balloon, and several series of static radiograph at rest, during squeezing and straining according to deflation of the balloon. RESULTS: Positive rate of barium leakage after barium insertion was significantly higher in incontinent patients than constipated or asymptomatic patients (P < 0.001, respectively). The degree of barium leakage was classified into mild in 18 patients with faecal incontinence, moderate in 4 and severe in 2. Constipated patients had more difficulty trying to expel a catheter than incontinent or asymptomatic patients (P=0.001, P=0.03). Twenty-four percent of patients with obstructed defaecation could not expel the balloon and 48% could not evacuate barium sulphate completely. The positive rate of morphological changes such as rectocele, internal intussusception and band formation was higher in constipated patients than incontinent or asymptomatic patients (P=0.01, P=0.04). CONCLUSION: The grade of barium leakage or balloon prolapse reflected the severity of faecal incontinence. The ability in rectal emptying of the balloon or barium sulphate also correlated with the degree of outlet obstruction. The authors concluded that the present defaecographic technique was useful for the assessment of faecal incontinence or functional outlet obstruction, and recommend it due to its simplicity.

Manometric and histologic assessment following proctocolectomy and straight enteroanal anastomosis in canines.

Serial manometric studies were performed in mongrel dogs before and after total colectomy, mucosal proctectomy and interposed jejunoanal anastomosis without pouch. Fecal continence and body weight gain were clinically satisfactory by 28 weeks after surgery. Even at 28 weeks after the mucosal proctectomy, the mean maximal resting anal sphincter pressure was significantly lower than the preoperative level (p less than 0.001). Neorectal compliance also decreased. The rectoanal inhibitory reflexes were not observed 2 weeks after the mucosal proctectomy but atypical to typical patterns gradually appeared up to 28 weeks following the mucosal proctectomy. Histologic examination showed no injury of anal sphincter muscles. Mild inflammation was found in the neorectal mucosal layer in all animals. Meissner's plexus in rectal muscular cuff was almost completely disrupted. These data suggested that there is certain limitation in restoration of anoneorectal function after mucosal protectomy and enteroanal anastomosis, though with gentle and careful operations.

Laparoscopic percutaneous jejunostomy for long term enteral access.

BACKGROUND: Patients suffering from upper gastrointestinal pathology may require jejunal feeding for adequate nutrition. A laparoscopically guided percutaneous jejunostomy offers a minimally invasive means of obtaining such feeding access. METHODS: Laparoscopic jejunostomy was performed in 32 patients. The most common indications were gastroparesis (n = 16), neurological deficits (n = 7), and proximal obstruction (n = 5). The proximal jejunum was affixed to the abdominal wall using intracorporeal and extracorporeal transabdominal sutures, allowing safe insertion of an 18-Fr Silastic dual-lumen tube. RESULTS: Laparoscopic jejunostomy was successfully completed for 28 patients; the procedure was converted to an open operation in four cases. Three of these four were among 14 patients undergoing the procedure who had a history of previous abdominal surgery. Major complications were observed in seven patients, including one reoperation and one death from aspiration pneumonia. Tube feeding was accomplished in all patients; progression to full enteral feeding proceeded without interruption in 20 patients. CONCLUSION: Laparoscopic jejunostomy can be performed with relative safety. Morbidity, though high, is usually related to preexisting disease. Previous abdominal surgery is not necessarily a contraindication to laparoscopic jejunostomy.

Effect of terminal ileal transposition on gallbladder bile composition following proctocolectomy.

Enterohepatic circulation of bile acid is impaired and the percentage of secondary bile acids in bile decreases after proctocolectomy and ileo-anal anastomosis. Moreover, the site-specific function and morphology of the terminal ileum are likely to be damaged by acute and chronic inflammation because the ileum is being used as a reservoir in this procedure. A jejunal segment was interposed between the terminal ileum and the anus to spare the terminal ileum from being used as a reservoir following proctocolectomy in dogs. We performed this study to investigate the effects of this procedure on gallbladder bile lipid composition. Adult mongrel dogs underwent either terminal ileal transposition procedure (n = 7) or conventional ileoanal anastomosis (n = 7) following two-stage proctocolectomy. The animals were laparotomized and gall-bladder bile was collected 12 weeks later. In the terminal ileal transposition group, the total bile acid concentration significantly decreased (P < 0.01), while the secondary bile acid percentage did not. In the conventional group, the percentage of secondary bile acid significantly decreased (P < 0.05), while the total bile acid concentration remained unchanged. Proximal transposition of the terminal ileum may have an advantage in preserving the percentage of secondary bile acid in gallbladder bile. This procedure effects bile lipid metabolism differently than conventional ileo-anal anastomosis.

Effect of radiotherapy on anorectal function in patients with cervical cancer.

PURPOSE: The acute and long-term effects of pelvic radiation on defecation were studied. METHOD: Anorectal function was assessed based on manometry and subjective symptoms in 31 patients with cervical cancer treated by radiotherapy alone. Sixteen of 31 patients were examined periodically before, during, and after radiotherapy (early group). Fifteen others were examined more than six months after completion of radiotherapy (late group). RESULTS: One-third of patients in both groups had symptoms, mainly diarrhea and increased stool frequency. Patients in the late group also suffered from disturbed gas-stool discrimination, urgency, a sense of residual stool, and soiling. Anal canal resting pressure was significantly higher after radiotherapy (47 +/- 15.5 mmHg) than before radiotherapy (36.3 +/- 12.5 mmHg; P < 0.05). The maximum tolerable volume decreased with radiation, from 163.3 +/- 45 before to 119.2 +/- 41.4 ml during, 112.7 +/- 36.6 ml immediately after, and 94.6 +/- 34.4 ml in the late group (P < 0.01). Rectal compliance also decreased over time and was lower in the early group (before, 5.7 +/- 1.3 ml/mmHg; P < 0.01; during, 4.6 +/- 2.2 ml/mmHg, P < 0.01; after, 3.7 +/- 1.4 ml/mmHg; P < 0.05) than the late group (2.1 +/- 1.5 ml/mmHg) and lower before than after in the early group (P < 0.01). Although rectal pressure initiating continuous desire to defecate did not change, the maximum tolerable pressure was significantly higher in the late group (81 +/- 19.5 mmHg) than during (59 +/- 16.8 mmHg) or after (59.9 +/- 16.9 mmHg) radiotherapy in the early group (P < 0.05). CONCLUSION: Radiation reduces the capacity of the rectal reservoir, even in asymptomatic patients. These changes develop during radiotherapy and progress over time.

Recovery of fasted and fed gastrointestinal motility after open versus laparoscopic cholecystectomy in dogs.

OBJECTIVE: The authors investigate the recovery of gastrointestinal motility in the fed and fasted state after laparoscopic and open cholecystectomy. SUMMARY BACKGROUND DATA: Clinical recovery after laparoscopic cholecystectomy is known to be more rapid than after conventional open cholecystectomy. However, the actual effect of a laparoscopic approach on gastrointestinal motility, particularly fed-state motility, is not well investigated. METHODS: Laparoscopic (LAP, n=6) or open (OPEN, n=6) cholecystectomy was performed in 12 dogs. Bipolar recording electrodes were placed on the antrum, small intestine, and the transverse and descending colon, and fasting myoelectric data were recorded after operation. Solid meal gastric emptying studies were performed before surgery and on postoperative days 1 and 2. Transit time studies were performed using 10 radiopaque markers. RESULTS: Gastric emptying was significantly delayed in the OPEN group at 120 minutes on postoperative day 1 compared with pre-operative emptying (p<0.05), but was not delayed on postoperative day 2. Gastric emptying was not delayed in the LAP group after operation. Transit time was the same between groups. Gastric dysrhythmias were more frequent on postoperative day 3 (p<0.05) in the OPEN group. There were no significant differences in the presence, cycle length, or propagation velocity of the migrating motor complex on any postoperative day. Discrete or continuous electrical response activity in the colon was observed by postoperative day 1 in both groups. CONCLUSIONS: Fed-state motility is the only parameter for which laparoscopic cholecystectomy showed an improvement in postoperative recovery. Recovery of fasted gastrointestinal motility in dogs is equally rapid after either operation.

Gastrointestinal recovery following laparoscopic vs open colon surgery.

BACKGROUND: We prospectively studied the recovery of gastrointestinal motility in patients undergoing laparoscopic (LAP, n = 7) or open (OPEN, n = 7) colon resections. METHODS: At operation, bipolar recording electrodes were placed on the proximal and distal antrum, the proximal site of the colonic anastomosis, and the rectosigmoid for postoperative myoelectric recordings. RESULTS: Shorter postoperative hospitalization and earlier resumption of a regular diet of the LAP group just barely failed to achieve significant differences when compared with the OPEN group (p = 0.091, p = 0.050, respectively). There were no differences between groups for slow wave frequency, amplitude, or dysrhythmias in the antrum, nor for return of discrete (DERA) and continuous (CERA) electrical response activity in the colon. Percentage of slow waves with spike activity tended to increase with passage of time postoperatively in both groups. There was a significant difference between POD 3 and 7+ in the LAP group (p < 0.05). However, there were no significant differences in the percentage of slow waves with spike activities between groups on any postoperative day. CONCLUSIONS: The potential benefits of using a laparoscopic approach to colon resection are not clearly confirmed by these data. While such an approach may possibly result in shorter hospitalization, it appears to offer at best only modest increases in the rapidity of recovery of gastrointestinal function.

Effect of terminal ileal transposition on intestinal absorption following proctocolectomy.

A terminal ileal transposition procedure, in which a distal jejunal segment is interposed between the terminal ileum and the anus following proctocolectomy, is described. Adult mongrel dogs had either terminal ileal transposition (n = 5) or ileoanal anastomosis (n = 6) following two-stage proctocolectomy. Untreated dogs were used as controls (n = 7). Twelve weeks after the second-stage operation, a perfusion study was performed. After terminal ileal transposition the transposed terminal ileum showed a high absorptive capability for sodium, chloride and bile acids (P < 0.05, P < 0.05 and P < 0.001 respectively). After ileoanal anastomosis the absorptive capability of the terminal ileum was not enhanced significantly. In the mid-jejunum, the absorption of bile acids, chloride and glucose was enhanced (all P < 0.05) only after terminal ileal transposition. Terminal ileal transposition improves the absorptive capability of the terminal ileum and the mid-jejunum compared with conventional ileoanal anastomosis in this model.

Traumatic rupture of hepatic hemangioma.

Although hepatic hemangioma is common, its rupture after trauma is rare. We report a 47-year-old woman with a traumatic hepatic hemangioma rupture following a traffic accident who successfully underwent operation. Only four cases of hepatic hemangioma rupture caused by blunt trauma have been reported including this one. Each patient (two men and two women) had a giant right lobe hemangioma. The causal injury included a traffic accident in two, a fall in one, and minor trauma in another. Three patients underwent surgery, and one was conservatively managed. All the patients survived.

Gallstone formation and gallbladder bile composition after colectomy in dogs.

A high prevalence of gallstones has been described in patients following colectomy. The aim of this study was to examine whether lithogenicity is attributed to colectomy. In the present study, changes in gallbladder bile composition and the mechanism of gallstone formation after colectomy were examined in dogs. Ten mongrel dogs underwent restorative proctocolectomy. Seven dogs which received sham operations served as controls. Over a 12-week postoperative period, samples of gallbladder bile, formed gallstones and serum were collected and analyzed. In 7 of the 10 (70%) colectomized dogs, gallstones were found in the gallbladder, while the control dogs had no stones. Macroscopically the gallstones were similar to black pigment stones observed in humans. Chemical analysis and Fourier transform-infrared spectroscopy examination revealed that the stones were composed mainly of sodium bilirubinate and proteins, with minor amounts of calcium salts and cholesterol. Significant increases in biliary pH and concentrations of ionized calcium and unconjugated bilirubin were observed in the gallbladder bile of the colectomy group compared with that of the control group. The total bile acid and total bilirubin concentrations were significantly decreased in the colectomy group. Cholesterol crystal nucleation did not occur. The inhibitory effect of gallbladder bile on calcium carbonate precipitation in an in vitro assay system was preserved even after colectomy. In conclusion, proctocolectomy increases the concentration of unconjugated bilirubin in gallbladder bile and induces pigment gallstones which are composed mainly of sodium bilirubinate and proteins since calcium ions and cholesterol are stabilized in dogs.