John A. Coller

A clinical trial of antioxidant vitamins to prevent colorectal adenoma

BACKGROUND People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer. METHODS We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo; beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations. RESULTS Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location. CONCLUSIONS The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.

Sacral nerve stimulation for fecal incontinence: Results of a 120-patient prospective multicenter study

Background:Sacral nerve stimulation has been approved for use in treating urinary incontinence in the United States since 1997, and in Europe for both urinary and fecal incontinence (FI) since 1994. The purpose of this study was to determine the safety and efficacy of sacral nerve stimulation in a large population under the rigors of Food and Drug Administration-approved investigational protocol. Methods:Candidates for SNS who provided informed consent were enrolled in this Institutional Review Board-approved multicentered prospective trial. Patients showing ≥50% improvement during test stimulation received chronic implantation of the InterStim Therapy (Medtronic; Minneapolis, MN). The primary efficacy objective was to demonstrate that ≥50% of subjects would achieve therapeutic success, defined as ≥50% reduction of incontinent episodes per week at 12 months compared with baseline. Results:A total of 133 patients underwent test stimulation with a 90% success rate, and 120 (110 females) of a mean age of 60.5 years and a mean duration of FI of 6.8 years received chronic implantation. Mean follow-up was 28 (range, 2.2–69.5) months. At 12 months, 83% of subjects achieved therapeutic success (95% confidence interval: 74%–90%; P < 0.0001), and 41% achieved 100% continence. Therapeutic success was 85% at 24 months. Incontinent episodes decreased from a mean of 9.4 per week at baseline to 1.9 at 12 months and 2.9 at 2 years. There were no reported unanticipated adverse device effects associated with InterStim Therapy. Conclusion:Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with FI.

The essential genome of a bacterium

Caulobacter crescentus is a model organism for the integrated circuitry that runs a bacterial cell cycle. Full discovery of its essential genome, including non‐coding, regulatory and coding elements, is a prerequisite for understanding the complete regulatory network of a bacterial cell. Using hyper‐saturated transposon mutagenesis coupled with high‐throughput sequencing, we determined the essential Caulobacter genome at 8 bp resolution, including 1012 essential genome features: 480 ORFs, 402 regulatory sequences and 130 non‐coding elements, including 90 intergenic segments of unknown function. The essential transcriptional circuitry for growth on rich media includes 10 transcription factors, 2 RNA polymerase sigma factors and 1 anti‐sigma factor. We identified all essential promoter elements for the cell cycle‐regulated genes. The essential elements are preferentially positioned near the origin and terminus of the chromosome. The high‐resolution strategy used here is applicable to high‐throughput, full genome essentiality studies and large‐scale genetic perturbation experiments in a broad class of bacterial species.

Anal complications in Crohn's disease.

Anal fissures, fistulas, and abscesses occurred as complications in 22 per cent of our population of 1,098 patients with Crohns disease. Crohns colitis was much more frequently associated with an anal lesion than Crohns disease of the small bowel (52 per cent vs. 14 per cent). When an anal lesion is the manifesting sign, Crohns disease will soon develop elsewhere in the intestine. Since these lesions frequently herald the onset of intestinal Crohns disease, the physician must always be aware of the possibility of inflammatory bowel disease when dealing with suspicions anal lesions.

Laparoscopic resection for diverticular disease

PURPOSE: The role of laparoscopic surgery in treatment of patients with diverticulitis is unclear. A retrospective comparison of laparoscopic with conventional surgery for patients with chronic diverticulitis was performed to assess morbidity, recovery from surgery, and cost. METHODS: Records of patients undergoing elective resection for uncomplicated diverticulitis from 1992 to 1994 at a single institution were reviewed. Laparoscopic resection involved complete intracorporeal dissection, bowel division, and anastomosis with extracorporeal placement of an anvil. RESULTS: Sigmoid and left colon resections were performed laparoscopically in 25 patients and by open technique in 17 patients by two independent operating teams. No significant differences existed in age, gender, weight, comorbidities, or operations performed. In the laparoscopic group, three operations were converted to open laparotomy (12 percent) because of unclear anatomy. Major complications occurred in two patients who underwent laparoscopic resection, both requiring laparotomy, and in one patient in the conventional surgery group who underwent computed tomographic-guided drainage of an abscess. Patients who underwent laparoscopic resection tolerated a regular diet sooner than patients who underwent conventional surgery (3.2±0.9vs.5.7±1.1 days;P<0.001) and were discharged from the hospital earlier (4.2±1.1vs.6.8±1.1 days;P<0.001). Overall costs were higher in the laparoscopic group than the open surgery group (

Long-term durability of sacral nerve stimulation therapy for chronic fecal incontinence

10,230±49.1vs.

Long-Term efficacy and safety of sacral nerve stimulation for fecal incontinence

7,068±37.1;P<0.001) because of a significantly longer total operating room time (397±9.1vs.115±5.1 min;P<0.001). Follow-up studies with a mean of one year revealed two port site infections in the laparoscopic group and one wound infection in the open group. Of patients undergoing conventional resection, one patient experienced a postoperative bowel obstruction that was managed nonoperatively, and, in one patient, an incarcerated incisional hernia developed that required urgent laparotomy. CONCLUSIONS: Laparoscopic resection in patients with chronic diverticulitis is safe, with faster recovery and shorter hospital stay compared with conventional open surgery. Higher cost of operating room usage time makes the laparoscopic technique difficult to justify economically. Simplification of operating room use and better case selection may improve cost-effectiveness of the laparoscopic approach.

The Fate of the Ileal Pouch in Patients Developing Crohn’s Disease

BACKGROUND: Limited data have been published regarding the long-term results of sacral nerve stimulation, or sacral neuromodulation, for severe fecal incontinence. OBJECTIVES: The aim was to assess the outcome of sacral nerve stimulation with the use of precise tools and data collection, focusing on the long-term durability of the therapy. Five-year data were analyzed. DESIGN: Patients entered in a multicenter, prospective study for fecal incontinence were followed at 3, 6, and 12 months and annually after device implantation. PATIENTS: Patients with chronic fecal incontinence in whom conservative treatments had failed or who were not candidates for more conservative treatments were selected. INTERVENTIONS: Patients with ≥50% improvement over baseline in fecal incontinence episodes per week during a 14-day test stimulation period received sacral nerve stimulation therapy. MAIN OUTCOME MEASURES: Patients were assessed with a 14-day bowel diary and Fecal Incontinence Quality of Life and Fecal Incontinence Severity Index questionnaires. Therapeutic success was defined as ≥50% improvement over baseline in fecal incontinence episodes per week. All adverse events were collected. RESULTS: A total of 120 patients (110 women; mean age, 60.5 years) underwent implantation. Seventy-six of these patients (63%) were followed a minimum of 5 years (maximum, longer than 8 years) and are the basis for this report. Fecal incontinence episodes per week decreased from a mean of 9.1 at baseline to 1.7 at 5 years, with 89% (n = 64/72) having ≥50% improvement (p < 0.0001) and 36% (n = 26/72) having complete continence. Fecal Incontinence Quality of Life scores also significantly improved for all 4 scales between baseline and 5 years (n = 70; p < 0.0001). Twenty-seven of the 76 (35.5%) patients required a device revision, replacement, or explant. CONCLUSIONS: The therapeutic effect and improved quality of life for fecal incontinence is maintained 5 years after sacral nerve stimulation implantation and beyond. Device revision, replacement, or explant rate was acceptable, but future efforts should be aimed at improvement.

Network Modeling Reveals Prevalent Negative Regulatory Relationships between Signaling Sectors in Arabidopsis Immune Signaling

BACKGROUND AND OBJECTIVE: Sacral nerve stimulation is effective in the treatment of urinary incontinence and is currently under Food and Drug Administration review in the United States for fecal incontinence. Previous reports have focused primarily on short-term results of sacral nerve stimulation for fecal incontinence. The present study reports the long-term effectiveness and safety of sacral nerve stimulation for fecal incontinence in a large prospective multicenter study. DESIGN AND METHODS: Patients with fecal incontinent episodes more than twice per week were offered participation in this multicentered prospective trial. Patients showing ≥50% improvement during test stimulation were offered chronic implantation of the InterStim Therapy system (Medtronic; Minneapolis, MN). The aims of the current report were to provide 3-year follow-up data on patients from that study who underwent sacral nerve stimulation and were monitored under the rigors of an Food and Drug Administration-approved investigational protocol. RESULTS: One hundred thirty-three patients underwent test stimulation with a 90% success rate, of whom 120 (110 females) with a mean age of 60.5 years and a mean duration of fecal incontinence of 7 years received chronic implantation. Mean length of follow-up was 3.1 (range, 0.2–6.1) years, with 83 patients completing all or part of the 3-year follow-up assessment. At 3 years follow-up, 86% of patients (P < .0001) reported ≥50% reduction in the number of incontinent episodes per week compared with baseline and the number of incontinent episodes per week decreased from a mean of 9.4 at baseline to 1.7. Perfect continence was achieved in 40% of subjects. The therapy also improved the fecal incontinence severity index. Sacral nerve stimulation had a positive impact on the quality of life, as evidenced by significant improvements in all 4 scales of the Fecal Incontinence Quality of Life instrument at 12, 24, and 36 months of follow-up. The most common device- or therapy-related adverse events through the mean 36 months of follow-up included implant site pain (28%), paresthesia (15%), change in the sensation of stimulation (12%), and infection (10%). There were no reported unanticipated adverse device effects associated with sacral nerve stimulation therapy. CONCLUSIONS: Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with fecal incontinence. These data support long-term safety and effectiveness to 36 months.

Indeterminate colitis predisposes to perineal complications after ileal pouch-anal anastomosis.

PURPOSERecent studies have suggested that a subset of patients with Crohn’s colitis may have a favorable outcome after ileal pouch-anal anastomosis and have advocated elective ileal pouch-anal anastomosis in selected patients with Crohn’s disease. We have not offered ileal pouch-anal anastomosis to patients with known Crohn’s disease, but because of the overlap in clinical presentation of ulcerative colitis and indeterminate colitis, some patients receiving an ileal pouch-anal anastomosis are subsequently found to have Crohn’s disease. We review our experience with these patients to identify potential preoperative predictors of ultimate pouch failure.METHODSPatients with a final diagnosis of Crohn’s disease were identified from an ileal pouch-anal anastomosis registry. These patients are followed prospectively. Preoperative and postoperative clinical and pathologic characteristics were evaluated as predictors of outcome. Median (range) values are listed.RESULTSThirty-two (18 females) patients (4.1 percent) with a final diagnosis of Crohn’s disease were identified from a registry of 790 ileal pouch-anal anastomosis patients (1980–2002). Patients underwent ileal pouch-anal anastomosis in two stages (11 patients) or three stages (21 patients). The preoperative diagnosis was ulcerative colitis in 24 patients and indeterminate colitis in 8 patients. Median follow-up was 153 (range, 13–231) months. The median time from ileal pouch-anal anastomosis to diagnosis of Crohn’s disease was 19 (range, 0–188) months. Complications occurred in 93 percent, including perineal abscess/fistula (63 percent), pouchitis (50 percent), and anal stricture (38 percent). Pouch failure (excision or current diversion) occurred in nine patients (29 percent) at a median of 66 (range, 6–187) months. Two of these 9 patients had preoperative anal disease (not significant). Comparing patients with failed pouches (n = 9) to patients with functioning pouches (n = 23), post-ileal pouch-anal anastomosis perineal abscess (67 vs. 26 percent, P = 0.05) and pouch fistula (89 vs. 30 percent, P = 0.01) were more commonly associated with pouch failure. Preoperative clinical, endoscopic, and pathologic features were not predictive of pouch failure or patient outcome. For those with a functional pouch, 50 percent have been or are currently on medication to treat active Crohn’s disease. This group had six bowel movements in 24 (range, 3–10) hours, with leakage in 60 percent and pad usage in 45 percent.CONCLUSIONSPatients who undergo ileal pouch-anal anastomosis and are subsequently found to have Crohn’s disease experience significant morbidity. Preoperative characteristics, including the presence of anal disease, were not predictive of subsequent pouch failure. We choose not to recommend the routine application of ileal pouch-anal anastomosis in any subset of patients with known Crohn’s disease.