The role of ¹8fluoro-deoxy glucose combined position emission and computed tomography in the clinical management of anal squamous cell carcinoma.

AIM: Anal squamous cell carcinoma (SCC) is uncommon in the western world but continues to increase in incidence. Optimal treatment and outcome are dependent upon pretreatment staging strategies. We evaluate the role of ¹8fluoro-deoxyglucose (¹8FDG) combined position emission and computed tomography (PETCT) in the management of anal SCC. METHOD: Patients with a histologically confirmed anal SCC underwent standard staging investigations, including computed tomography, Magnetic resonance imaging and examination under anaesthetic. A tumour, node, metastasis (TNM) system was used. All patients subsequently underwent additional whole-body ¹8FDG PETCT scanning. Management was planned accordingly, blinded to ¹8FDG PETCT findings, at a multidisciplinary meeting, and reviewed again following disclosure of PETCT results. RESULTS: Forty patients (24 men), with a median age of 57 years (range 38-87 years), were prospectively recruited. All primary tumours were ¹8FDG avid. PETCT did not alter the T stage but did result in disease upstaging (N and M stages). Management was altered in five (12.5%) patients: one patient was identified to have an isolated distant metastasis, and four patients had ¹8FDG-avid lymph nodes not otherwise detected, all of which were tumour-positive on fine needle aspiration cytology/biopsy. CONCLUSION: PETCT upstages anal SCC and influences subsequent management. PETCT should be considered in the staging of anal SCC, although the definitive benefit of such a strategy requires further evaluation.

Analysis of innervation of human mesenteric vessels in non-inflamed and inflamed bowel--a confocal and functional study.

We investigated the distribution and density of perivascular nerves in human mesenteric arteries and veins and their responses to noradrenaline (NA), ATP and neuropeptide Y (NPY) in control (non-inflamed) and inflamed bowel, using confocal microscopy and in vitro pharmacology. The density of innervation at the adventitial-medial border of arteries and within the medial muscle coat of veins was increased in inflammatory bowel disease (IBD). Expression of markers for both sympathetic nerves and sensory-motor nerves was significantly increased in IBD. Calcitonin gene-related peptide-containing sensory-motor nerves were present in control arteries and IBD, but not in control veins. The density of 5-hydroxytryptamine-containing nerves was variable in controls, but consistently increased (three to four times) in IBD. Vasoactive intestinal peptide (VIP) expression increased (doubled) in arteries and veins. Arteries and veins contracted to NA and ATP, but only veins constricted to NPY. ATP contractions were reduced in arteries and veins in IBD, while contractions to NA were only slightly reduced. Neuropeptide Y induced significantly greater (20%) contractions of IBD veins. In summary, the density of sympathetic and sensory-motor innervation of both mesenteric arteries and veins was increased in IBD. Both 5-hydroxytryptamine and VIP immunoreactivity were also increased. The responses of both arteries and veins to ATP, and to a lesser extent NA, were reduced in IBD while responses to NPY were greater in veins. Decreased responses to ATP indicate changes in purinergic-mediated transmission in the pathological state.

Improving the morbidity of anorectal injury from pelvic radiotherapy.

OBJECTIVE: Radiation anorectal injury due to pelvic radiotherapy for non intestinal cancer is a significant cause of morbidity which may limit the treatment dose required. Conservative treatment options are of limited value and surgery is reserved only for the most severe complications. This review addresses radioprotection of the anorectum and aims to increase awareness amongst surgeons of the strategies that have been in practice in order to minimize the side-effects of radiotherapy while preserving its therapeutic efficacy. METHODS: This review is based on a literature search (Medline and NLM PubMed) with manual cross-referencing of all articles related to anorectal radiation injury. RESULTS: Optimization of radiation dose, the use of radioprotective agents and improvement in radiation delivery are the main areas of development. There are few data on the potential of altered fractionation schedules in reducing anorectal injury. A few phase I and II studies suggest that the pharmacological agents amifostine and misoprostol could be beneficial in limiting radiation damage but larger phase III studies are awaited. CONCLUSION: The introduction of 3-dimensional conformal radiation therapy and intensity modulated radiation therapy has been the most significant advance in reducing radiation morbidity.

Changes in vasoconstrictor and vasodilator neurotransmitters in nerves supplying arterioles in developing colorectal polyps.

OBJECTIVE: To examine the changes that occur in the immunohistochemistry of vasoconstrictor and vasodilator transmitters in nerves supplying early and advanced colorectal polyps. SUBJECTS AND METHODS: We studied the perivascular innervation of submucosal arterioles of colorectal polyps (n = 18) and the innervation of the epithelial layer of polyps compared to normal controls (n=8), using immunohistochemical markers for the neurotransmitters; noradrenaline (NA) (marker used; tyrosine hydroxylase (TH)), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related polypeptide (CGRP). (Advanced polyps; villous adenomas>1.5 cm, polyps with severe dysplasia or partial carcinoma). RESULTS: In submucosal arterioles there was a progressive decrease from controls through early polyps to advanced polyps in TH and NPY perivascular immunoreactivity (P<0.015 for both). VIP and SP immunoreactivity was higher in early polyps compared to controls, but markedly reduced in advanced polyps (P<0.05 for VIP). Sparse CGRP immunoreactivity was present in polyps only. Neural VIP and SP immunoreactivity in the lamina propria of polyp mucosa was more intense than in controls. CONCLUSION: There is a decrease in vasoconstrictor neurotransmitters NPY and NA (shown by TH) around submucosal arterioles of both early and advanced polyps, but an increase in the vasodilator neurotransmitters, particularly VIP, in early colorectal polyps. These results suggest a predominantly vasodilatory neural influence in early polyps, perhaps indicating a mechanism that maintains polyp growth.

Is MSI-H of value in predicting the development of metachronous colorectal cancer?

Nearly 10% of patients with colorectal cancer (CRC) develop a metachronous cancer after curative resection of their primary malignancy, however identifying these patients is problematic. Although microsatellite instability (MSI) is associated with the development of multiple CRC, this is predominantly seen in those with hereditary non-polyposis colon cancer (HNPCC). This study has examined the value of MSI analysis in identifying patients at risk of developing metachronous cancer from the general population. MSI analysis was performed at the Bat25, Bat26, Bat40, D2S123, D5S346 and D17S250 loci using polymerase chain reaction and single-stranded conformational polymorphism on DNA extracted from 62 specimens taken from 49 patients with metachronous CRC, and from 71 primary single CRCs. MSI status was classified into MSI-H, MSI-L and MSS. MSI-H was more prevalent in metachronous cancers, 34/62 compared to 8/71 single cancers (P < 0.0001). The incidence of MSI-H from proximal colon cancers in index metachronous group, 4/22 was similar to single cancer group, 7/71 (P = 0.28), however MSI-H was more commonly identified in index metachronous cancers located distal to the splenic flexure 9/22 than single cancers 1/71 (P < 0.0001). Patients presenting with MSI-H colorectal cancers distal to the splenic flexure are more likely to develop a metachronous cancer and will benefit from surveillance.

The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers.

There is increased incidence of microsatellite instability (MSI) in patients who develop multiple primary colorectal cancers (CRC), although the association with hereditary nonpolyposis colon cancer (HNPCC) is unclear. This study aims to evaluate the underlying genetic cause of MSI in these patients. Microsatellite instability was investigated in 111 paraffin-embedded CRCs obtained from 78 patients with metachronous and synchronous cancers, and a control group consisting of 74 cancers from patients with a single CRC. Tumours were classified as high level (MSI-H), low level (MSI-L) or stable (MSS). MLH1, MSH2 and MSH6 gene expression was measured by immunohistochemistry. Methylation of the MLH1 promoter region was evaluated in MSI-H cancers that failed to express MLH1, and mutational analysis performed in MSI-H samples that expressed MLH1, MSH2 and MSH6 proteins. The frequency of MSI-H was significantly greater in the multiple, 58 out of 111 (52%), compared to the single cancers, 10 out of 74 (13.5%), P < 0.01. Of the 32 patients from whom two or more cancers were analysed, eight (25%) demonstrated MSI-H in both cancers, 13 (41%) demonstrated MSI-H in one cancer and 11 (34%) failed to demonstrate any MSI-H. MSI-H single cancers failed to express MLH1 or MSH2 in seven out of nine (78%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in one out of 45 (2.2%) cases, all cancers expressed MSH6. MSI-H multiple cancers failed to express MLH1 or MSH2 in 21 out of 43 (48%) cases and MSI-L/MSS cancers failed to express MLH1 or MSH2 in four out of 32 (12.5%) cases. MSH6 expression was lost in five MSI-H multiple cancers, four of which also failed to express MLH1 or MSH2. Loss of expression of the same mismatch repair (MMR) gene was identified in both cancers from six out of 19 (31%) patients. Methylation was identified in 11 out of 17 (65%) multiple and three out of six (50%) single MSI-H cancers that failed to express MLH1. Mutational analysis of 10 MSI-H multiple cancers that expressed MLH1, MSH2 and MSH6 failed to demonstrate mutations in the MLH1 or MSH2 genes. We suggest that, although MSI-H is more commonly identified in those with multiple colorectal cancers, this does not commonly arise from a classical HNPCC pathway.

Anal intraepithelial neoplasia.

BACKGROUND: Anal intraepithelial neoplasia (AIN) is believed to be a precursor of anal squamous cell cancer and its incidence is rising in high-risk groups, particularly those infected with the human immunodeficiency virus (HIV). The natural history of AIN is unclear and management strategies are lacking. METHODS: This review is based on a literature search (Medline and PubMed) with manual cross-referencing of all articles related to AIN. RESULTS AND CONCLUSIONS: The aetiology of AIN is intricately linked with human papilloma viruses. The pathological processes involved in the progression of AIN are becoming clearer but the natural history, particularly the rate of progression to invasive cancer, remains unknown. There is no standard management for AIN and this is mainly due to difficulties in both diagnosis and treatment. A variety of treatment options have been tried with varying success. Surgery is associated with significant recurrence, particularly in HIV-positive patients. Non surgical approaches with imiquimod, photodynamic therapy and vaccination are appealing, and further work is required. Long-term follow-up of these patients is essential until the natural history of AIN becomes clearer.

Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability.

Micro-satellite instability (MSI) is relevant in the management of colorectal cancers (CRC) and relies on analysis of gene mutations, or production of the proteins involved in DNA mismatch repair (e.g. MLH1, MSH2). p53 mutation is also relevant in MSI, but high-level CRC (MSI-H) demonstrate fewer mutations than low-level (MSI-L) or stable (MSS) cancers. Recently, the importance of gene activity (transcription) in MSI has been identified, where rather than being mutated genes have been downregulated. In this study, 67 sporadic CRC and eight samples of normal bowel were analysed for MSI status (by SSCP) and levels of MLH1, MSH2 and p53 gene transcription (by RT-PCR and scanning densitometry). Micro-satellite instability correlated with gender and site, with more MSI-H CRC in females (P<0.02) and in the right colon (P<0.04). In MSI-H, p53 transcription was markedly reduced (P<0.003). Compared to normal bowel, MLH1 transcription was elevated in all cancers (P<0.01), while MSH2 transcription was elevated only in MSI-H (P<0.04). There was a direct correlation between MLH1 and MSH2 transcription (P<0.001). Although fewer mutations are reported in MSI-H than MSI-L/MSS, these results suggest that reduced p53 transcription might account for decreased tumour suppression in MSI-H. The direct correlation between MLH1 and MSH2 transcription suggests that control of these genes might be coordinated.

The clinical importance and prognostic implications of microsatellite instability in sporadic cancer.

AIMS: The genetic abnormality known as microsatellite instability (MSI), first identified in colorectal cancer in 1993, has subsequently been recognised in other malignancies. These cancers are caused by a defect in the nuclear mismatch repair system, allowing mutations to accumulate with every cellular division. Hereditary Non Polyposis Colon Cancers (HNPCC) and associated malignancies demonstrating MSI have a unique histological appearance, improved prognosis and altered response to chemotherapy and radiotherapy. This review examines the incidence of MSI and its clinical significance in commonly occurring solid malignancies. METHOD: A medline based literature search was performed using the key words 'Microsatellite Instability' and the name of the specific malignancy being investigated. Additional original papers were obtained from citations in those articles identified in the original medline search. RESULTS: MSI has been detected in many solid malignancies although the definition of instability applied has been variable. It is most commonly found in sporadic malignancies that also occur in the HNPCC syndrome such as colorectal, stomach, endometrial and ovarian cancer. MSI may impart a favorable prognosis in colorectal, gastric, pancreatic and probably oesophageal cancers but a poor prognosis in non small cell lung cancer. In clinical studies colorectal cancers demonstrating MSI respond better to chemotherapy while in vitro studies using MSI positive cell lines show resistance to radiotherapy and chemotherapy. CONCLUSION: MSI may be a useful genetic marker in prognosis and could be an influential factor in deciding treatment options. However, in many cancers its significance remains unclear and more evaluation is required.

Complicated diverticulosis.

"Uncomplicated" diverticulitis can be prevented from progressing into "complicated" diverticulitis by early diagnosis and active medical treatment. Complicated diverticulitis develops from a peridiverticular abscess, to a perforation with peritonitis, to fistulation into adjacent viscera, to luminal narrowing by inflammation or stricture formation causing obstruction. Computer tomography (CT) scanning is the diagnostic imaging modality when diverticulitis is suspected and allows percutaneous drainage of peridiverticular abscesses that will enhance the effect of antibiotic therapy with resolution of the acute episode in 75% of patients. Thus, an emergent or urgent operation is converted to an elective operation and a two-stage operative procedure, namely a temporary stoma and a second operation, is avoided. Interventional surgery is urgent for perforation and obstruction. While a Hartmann's resection and temporary colostomy has been the favoured operative procedure, under favourable conditions resection with primary anastomosis is preferable. Although a temporary stoma may be required with primary anastomosis, and hence the procedure is a two-stage one similar to a Hartmann's, the closure of the stoma is less demanding and has a lower morbidity. A single-stage resection and anastomosis is the standard elective treatment for symptomatic fistulas and strictures.

Pathogenesis and clinical management of hereditary non-polyposis colorectal cancer.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited genetic condition associated with microsatellite instability; it accounts for around 5 per cent of all cases of colorectal cancer. This review examines recent data on management strategies for this condition. METHODS: A Medline-based literature search was performed using the keywords 'HNPCC' and 'microsatellite instability'. Additional original papers were obtained from citations in articles identified by the initial search. RESULTS AND CONCLUSION: The Amsterdam criteria identify patients in whom the presence of an inherited mutation should be investigated. Those with a mutation should be offered counselling and screening. The role of prophylactic surgery has been superseded by regular colonoscopy, which dramatically reduces the risk of colorectal cancer. Screening for extracolonic malignancy is also advocated, but the benefits are uncertain. Chemoprevention may be of value in lowering the incidence of bowel cancer in affected patients, but further studies are required.

Possible absence of Helicobacter pylori in the early stages of duodenal ulceration.

BACKGROUND: Helicobacter pylori is thought to be a cause of duodenal ulceration, but there is some evidence that it is found less often in early than in later disease. AIM: To assess the presence of H. pylori in patients undergoing endoscopy for dyspepsia, with respect to their duration of symptoms. DESIGN: Retrospective case note review. METHODS: Patients were categorized as having a history greater or less than 6 months, and as H. pylori-positive or -negative, using biopsy rapid urease, culture and PCR tests. RESULTS: Thirty-two duodenal ulcer patients with a history >6 months were all H. pylori-positive according to the PCR test; the five with a shorter history were H. pylori-negative. No patient H. pylori-negative by PCR was positive by the other tests. DISCUSSION: H. pylori was (at least) less commonly present before 6 months. It is possible that H. pylori, although nearly always present after 6 months, is not present at the onset of the disease. Confirmation of this finding would imply that infection with the organism is not the cause of duodenal ulceration, but a factor producing recurrence and chronicity.

Preliminary evaluation of United Kingdom National Referral Guidelines for lower gastrointestinal tract cancer.

OBJECTIVE: To evaluate the efficiency of the criteria proposed by the National Referral Guidelines at selecting patients with lower gastrointestinal tract cancer for urgent outpatient assessment when compared with the standard method for prioritization. PATIENTS AND METHODS: Consecutive patients aged 50 and over referred to a colorectal unit were offered urgent or non-urgent outpatient appointments on the basis of the contents of the referral letter. Clinical information obtained during the outpatient consultation was used to identify those patients that satisfied the guideline criteria for urgent referral. Patients were investigated and the findings recorded. RESULTS: Of 247 patients who completed their investigations 18 were found to have lower gastrointestinal tract cancer. Urgent outpatient appointments were offered to 115 patients of whom 14 had cancer (P = 0.0067, sensitivity=78%). A total of 119 patients satisfied the guideline criteria for urgent referral, including 17 of the patients who were found to have cancer (P < 0.0001, sensitivity=94%). CONCLUSION: The criteria used in the guidelines provide an effective method for selecting patients with cancer for urgent assessment. Application of the guidelines by general practitioners can be recommended.

Regulation of matrix metalloproteinases in a model of colonic wound healing in a rabbit.

PURPOSE: Matrix metalloproteinases occur in the colon at an anastomosis but not in the normal colon. Matrix metalloproteinase synthesis can be regulated by cytokines, for example interleukin-1 beta and growth factors, such as transforming growth factor beta and basic fibroblast growth factor. The aim of this study was to investigate the regulation of matrix metalloproteinases at an anastomosis by identifying the cell types that synthesize matrix metalloproteinases, examining factors that might regulate their synthesis, determining whether they occur in an active form, and assessing the effect of suture type on these parameters. METHODS: An anastomosis was formed in the distal colon of rabbits using either polyglactin or polydioxanone and the animals were killed six hours or seven days later. The distribution of matrix metalloproteinases and cytokines and the cell types were assessed by immunohistochemistry. Matrix metalloproteinase-2, matrix metalloproteinase-3, and matrix metalloproteinase-9 were detected also by zymography. RESULTS: Immunohistochemistry showed that matrix metalloproteinases were restricted to the suture line. Although zymography demonstrated that matrix metalloproteinase-2 was present mainly in an active form, matrix metalloproteinase-9 and matrix metalloproteinase-3 were present in the pro-form. The active form of matrix metalloproteinase-3 occurred more often in the polydioxanone-sutured rabbits. With the exception of matrix metalloproteinase-9, the matrix metalloproteinases were synthesized by fibroblasts. Interleukin-1 beta and transforming growth factor beta were more widespread than in the normal colon and were localized adjacent to the matrix metalloproteinases. Basic fibroblast growth factor was also more widespread postoperatively but occurred deeper in the anastomosis than the matrix metalloproteinases. CONCLUSIONS: This study has shown that interleukin-1 beta and transforming growth factor beta may regulate the synthesis of the matrix metalloproteinases by fibroblasts and that minor differences that occur in the matrix metalloproteinase profile are dependent on the suture type.

Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ET(A) receptor antagonism.

Endothelin-1 (ET-1) is a vasoconstrictor peptide which stimulates proliferation in vitro in different cell types, including colorectal cancer cells. Raised ET-1 levels have been detected both on tissue specimens and in the plasma of patients with cancers. To investigate the role of ET-1 in colorectal cancer: (i) ET-1 plasma levels in patients with colorectal cancer were measured by radioimmunoassay: group 1 = controls (n = 22), group 2 = primary colorectal cancer only (n = 39), group 3 = liver metastases only (n = 26); (ii) ET-1 expression in primary colorectal cancer specimens (n =10) was determined immunohistochemically and (iii) the effect of intraportally infused antagonists to the two ET-1 receptors, ET(A) and ET(B), on the growth of liver metastases in a rat model was assessed. ET-1 plasma levels were significantly increased in both patients with primary tumour and patients with metastases, compared to controls (P < 0.01, 3.9 +/- 1.4, 4.5 +/- 1.5, vs. 2.75 +/- 1.37 pg/ml, respectively). Immunohistochemically, strong expression of ET-1 was found in the cytoplasm, stroma and blood vessels of cancers, unlike the normal colon where only the apical layer of the epithelium, vascular endothelial cells and surrounding stroma were positively stained. In the rat model, there was significant reduction in liver tumour weights compared to controls, following treatment with the ET(A) antagonist (BQ123) 30 min after the intraportal inoculation of tumour cells (P < 0.05). These results suggest ET-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ET(A) receptors. ET(A) antagonists are indicated as potential anti-cancer agents.

Anorectal injury following pelvic radiotherapy.

BACKGROUND: Current knowledge of the effects of radiation on the anorectum is based on a limited number of studies. Variability in delivery techniques, both currently and historically, combined with a paucity of prospective and randomized studies makes interpretation of the literature difficult. This review presents the existing evidence and identifies areas that require further work. METHODS: This review is based on a literature search (Medline and PubMed) and manual cross-referencing. RESULTS AND CONCLUSION: More than three-quarters of patients receiving pelvic radiotherapy experience acute anorectal symptoms and up to one-fifth suffer from late-phase radiation proctitis. About 5 per cent develop other chronic complications, such as fistula, stricture and disabling faecal incontinence. The risk of rectal cancer may be increased. Conservative treatment options are of limited value. Surgery may be considered if symptoms are severe, provided sphincter function is adequate and recurrent disease is excluded. Large prospective studies with accurate dosimetric data and long-term follow-up are needed to provide meaningful information on which to base new strategies to minimize the side-effects from radiotherapy.

Anorectal irradiation in pelvic radiotherapy: an assessment using in-vivo dosimetry.

The objectives of this study were to measure by in-vivo techniques the radiation doses received by the anorectum during pelvic radiotherapy and compare these with doses predicted by a GE TARGET treatment planning system. Nine patients with cancers of the prostate, bladder, cervix or uterus were planned with computed tomography (CT) using the TARGET system. A Scanditronix rectal probe containing five n-type photon-detecting diodes was placed in the anorectum during the planning CT scans. The probe position was standardized with the five diodes at 2 cm intervals from the anal verge. The probe diodes were calibrated for 10 MV photons. Doses were measured for each diode for two consecutive fractions in the first four patients and for five consecutive fractions in the remaining five. Thermoluminescent dosimeters were used initially to verify diode doses. The TARGET and diode measured doses were compared. In all patients diodes situated in the target volume were within 7% of predicted doses. This improved to 2.5% after measurement on five fractions. At the edges of the target volume, wide variability existed between measured and predicted doses (measured dose range -68% to +68% of predicted dose). Outside the target volume, considerable doses (up to 0.3 Gy per fraction) were measured in the anal canal, which were not predicted by TARGET. We conclude that TARGET planned doses are accurate within the confines of the target volume. The greatest variability was seen at the edges of the target volume, where dose can vary by 50% across a 1 cm distance in the anterior-posterior plane. TARGET does not account for scattered dose beyond the field edges and therefore underestimates the dose received by the anal canal.

A double-blind randomized placebo-controlled trial of oral indoramin to treat chronic anal fissure.

BACKGROUND: Indoramin is an alpha1-adrenoceptor antagonist and has been shown to reduce anal resting pressure. Its therapeutic potential has not been explored. The aim of this study was to determine the outcome of treatment with oral indoramin on patients with chronic anal fissure in the setting of a double-blind randomized placebo-controlled trial. METHODS: Twenty-three patients with chronic anal fissure were computer randomized to receive a 6-week course of oral indoramin (20 mg) or placebo in identical capsules, twice daily and with bulk-forming laxatives. Pain was assessed by a visual analogue scale from 0 to 10. Anal resting pressure, heart rate and blood pressure were recorded. Patients were reviewed 1 h after taking the capsule and at 2, 6 and 12 weeks thereafter. RESULTS: Fourteen patients were randomized to indoramin and 9 to placebo. Maximum anal resting pressure was reduced from a mean of 96.4 cm H2O (+/- 32) to 67.6 cm H2O (+/- 26), 1 h after indoramin (P=0.02) and there was no significant change after placebo. There were no significant changes in heart rate or blood pressure. Pain was reduced in the placebo group from a score of 4.9 to 2.0 after 6 weeks (P < 0.01) but not in the indoramin group. After 6 weeks, healing had occurred in one (7%) patient in the indoramin group and in 2 (22%) in the placebo group (P > 0.1). After 3 months, the chronic anal fissure in the indoramin group had recurred. The trial was terminated early because of poor healing rates. CONCLUSION: An oral dose of indoramin (20 mg) administered twice daily reduced anal resting pressure by 30% compared with pretreatment levels but was ineffective in healing chronic anal fissures.