Immune responses in advanced colorectal cancer following repeated intradermal vaccination with the anti-CEA murine monoclonal antibody, PR1A3: results of a phase I study.

BACKGROUND AND AIMS: The aim was to determine the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, PR1A3, in patients with advanced colorectal cancer. MATERIALS AND METHODS: Fifteen patients with advanced colorectal cancer received either 0.5-, 1.0- or 5.0-mg doses of PR1A3 mixed with 10% w/v Alum adjuvant (Superfos Biosector, Denmark) intradermally at 4-week intervals for 3 months. Patient serum was assessed for anti-idiotypic (Ab2), anti-anti-idiotypic (Ab3) and human anti-mouse antibody (HAMA) reactivity. Peripheral blood mononuclear cell (PBMC) proliferation with phytohaemagglutinin (PHA), CEA and PR1A3, stimulated IL-2, IL-4 and IFN-gamma levels and PR1A3-stimulated IL-2 receptor expression during immunotherapy were determined. Comparisons were made with 16 age-matched controls without malignant disease. RESULTS: Hyperimmune sera from 12 of the 15 patients showed Ab2 reactivity with no detectable Ab3 responses. Strong HAMA reactivity was recorded in 7 of the 15 cases with no adverse clinical effect. Delayed-type hypersensitivity (DTH) responses developed in 12 of the 15 patients. Pre-treatment PBMC proliferation with PHA was subnormal in each patient compared with controls, becoming normal (or supranormal) in all patients during immunisation (P<0.001). PBMC proliferation with CEA and PR1A3 increased during immunotherapy (P<0.001) along with stimulated production of IL-2, IFN-gamma and IL-2 receptor expression. Progressive disease was observed in 14 of the 15 patients with minimal toxicity. CONCLUSION: PR1A3 generated limited idiotypic responses but robust DTH reactivity in most patients. In vitro PBMC proliferation with mitogens and recall antigens is greatly increased during the course of immunisation, with a shift in stimulated cytokine profile.

Alteration of anal sphincter morphology following vaginal delivery revealed by multiplanar anal endosonography.

OBJECTIVE: To assess morphologic change in the anal sphincters in the absence of endosonographic evidence of trauma after vaginal delivery. DESIGN: Prospective observational study. SETTING: District general hospital. POPULATION: Consecutively booked nulliparous pregnant women attending antenatal clinic. METHODS: All women were examined using three-dimensional anal endosonography, simple manometry and had questionnaire assessment of incontinence before and after delivery. MAIN OUTCOME MEASURES: Components of the anal canal were measured in the axial, sagittal and coronal planes and paired pre- and post-delivery examinations were compared. Any changes were related to changes in continence and anal canal manometry. RESULTS: Twenty-two women had a vaginal delivery and no endosonographic evidence of perineal trauma after delivery. After delivery, there was significant shortening of the length of the anterior external anal sphincter [EAS] (mean 21.7 vs 20.5 mm, P = 0.02) when measured in the sagittal plane, which increased in anterior angulation with respect to the axis of the anal canal (10 degrees vs 13.8 degrees, P = 0.03). In the axial plane, no change was seen in the thickness of any of the sphincter components after delivery. None of these morphologic changes correlated with changes in manometry or continence score. CONCLUSIONS: Anal sphincter morphology changes after an otherwise atraumatic vaginal delivery. This change does not correlate with any functional symptoms.

Endosonographic anatomy of the normal anal canal compared with endocoil magnetic resonance imaging.

PURPOSE: This study was designed to clarify the sonographic anatomy of the normal anal canal by comparison with endoanal magnetic resonance imaging, to determine agreement between these imaging modalities and interobserver error in measuring layer thickness. METHODS: Three-dimensional endosonographic and endocoil magnetic resonance images of the anal canal were obtained in four males and five nulliparous females aged 22 to 34 years. Images were analyzed at similar levels throughout the canal using a graphics-overlay technique to compare sonographic with magnetic resonance images. Measurements were taken at one level for agreement analysis between modalities and for interobserver variability in the measurement of the thickness of the main anal canal layers. RESULTS: The muscularis submucosae ani, muscle bundles in the longitudinal muscle layer, and puboanalis were identified on sonography. The outer border of the external sphincter was demarcated by an interface reflection with ischioanal fat. Clarification of the external sphincter anatomy allowed excellent correlation (Ri = 0.96) for the assessment of thickness. There was excellent correlation for the interobserver measurement of the external and internal sphincters and the submucosal width on endosonography, but there was poor correlation for the longitudinal muscle (0.12). CONCLUSION: The overlay technique has improved endosonographic interpretation, and measurement of external sphincter thickness has been validated both by comparison with magnetic resonance and on interobserver agreement.

Assessment of external anal sphincter morphology in idiopathic fecal incontinence with endocoil magnetic resonance imaging.

The failure of external anal sphincter repair may relate to sphincter atrophy where muscle fibers are replaced by fat, seen on MRI due to the differing signals returned by fat and muscle tissue. Manometry, electrophysiology, and MRI with an endocoil were performed on 34 fecally incontinent patients with intact sphincters on endosonography. The area of the external sphincter was measured in the midcoronal plane, and the percentage fat content calculated. Sphincter muscle area correlated strongly with squeeze pressure (P < 0.001) but not with percentage fat content. There was no relationship between percentage fat and age, weight, anal sensation, squeeze pressure, sphincter length or width, or pudendal nerve terminal motor latency. There was a trend for smaller sphincters to contain a higher percentage fat content (P = 0.059). MRI has established a relationship between function and external sphincter bulk, but not fat content, although smaller muscles may contain more fat.

Endocoil magnetic resonance imaging quantification of external anal sphincter atrophy.

BACKGROUND: Anal function depends on the integrity and quality of the sphincter muscles. The diagnosis of external anal sphincter atrophy on endocoil magnetic resonography has been associated with poor outcome from sphincter repair, although the imaging criteria for atrophy remain unclear. METHODS: Women with intact sphincters on endosonography and either normal (more than 60 cm H(2)O) (n = 9) or low (n = 16) squeeze pressures had endocoil magnetic resonography and electromyography. The area and fat content of the external anal sphincter and puborectalis were measured on mid-coronal magnetic resonography and images were graded as showing normal, intermediate or advanced atrophy. The definition of the external anal sphincter on endosonography and the thickness of the internal anal sphincter were also assessed. RESULTS: Women with a normal anal squeeze pressure had a larger external anal sphincter cross-sectional area (mean(s.d.) 240(56) versus 193(62) mm(2); P = 0.01) with a lower mean fat content (mean(s.d.) 23(4) versus 30(6) per cent; P < 0.001) than those with low squeeze pressures. There was an overall correlation between squeeze pressure, cross-sectional area (r = 0.32, P = 0.02) and fat content (r = - 0.51, P < 0.001). Patients with a thin (less than 2 mm) internal anal sphincter and/or a poorly defined external sphincter on endosonography were more likely to have atrophy (positive predictive value 74 per cent). CONCLUSION: : Potential endosonographic markers for external anal sphincter atrophy are suggested, and a visual scale for endocoil magnetic resonographic assessment has been validated.

Anal sphincter damage after vaginal delivery using three-dimensional endosonography.

OBJECTIVE: To determine the incidence and functional consequences of external sphincter trauma compared with other perineal structures using a novel imaging technique, three-dimensional endosonography. METHODS: Fifty-five nulliparous women (mean age 30 years, range 18--47 years) had three-dimensional anal endosonography, anal manometry, and questionnaire assessment of continence at a median gestation of 33 weeks (23--42 weeks) and 10 weeks (7--22 weeks) after delivery. RESULTS: There was ultrasound evidence of postpartum trauma in 13 of 45 women who had a vaginal delivery (29%, confidence interval [CI] 16%, 44%), involving the external sphincter in five (11%, CI 4%, 24%), the puboanalis in nine (20%, CI 10%, 35%), and the transverse perineii in three (7%, CI 1%, 18%). In four, more than one structure was damaged. External sphincter trauma was associated with a significant decrease in squeeze pressure (P =.035) and an increase in incontinence score (P =.02) compared with those without trauma. Tears to the puboanalis or transverse perineii only did not affect pressure or incontinence scores. Coronal imaging of the external anal sphincter was a useful adjunct to the assessment of trauma. CONCLUSION: The overall incidence of trauma to the sphincter complex was similar to that of previous reports, although actual damage to the external sphincter was less common and represented the only functionally significant component.

Multiplanar anal endosonography--normal anal canal anatomy.

INTRODUCTION: Volume acquisition during anal ultrasound enables multiplanar imaging of the anal canal. The normal ultrasonic multiplanar appearance of the anal canal is described and gender differences in canal anatomy are highlighted. METHODS: Ten male and 12 female normal volunteers (mean ages 31.5 years (s.d. 5.9) and 31.2 (s.d. 6.7)) had three-dimensional anal endosonography (3-D AES). Each volume dataset was seeded in the axial plane facilitating multiplanar identification of known anatomical structures. RESULTS: The anterior external anal sphincter (EAS) was significantly longer in men than women 30.1 mm (3.9) vs 16.9 mm (7.4) (P < 0.001). There was no difference in the length of the puborectalis 24.7 mm (6.4) vs 24 mm (5) (P=0.78) in men compared with women. The cranial extent of the anterior EAS was tilted forward in both sexes. The angle formed by the anterior EAS and the longitudinal axis of the anal canal was more acute in men than in women (11.1 degrees vs 18.6 degrees; P=0.007). Dataset volume seeding of familiar structures in the axial plane allowed the multiplanar endosonographic anatomy to be described. CONCLUSIONS: Multiplanar AES has enabled detailed longitudinal measurement of the components of the anal canal and has revealed important gender differences. The multiplanar ultrasonic appearance of the normal anal canal has been described for the first time.

Gender differences in the longitudinal pressure profile of the anal canal related to anatomical structure as demonstrated on three-dimensional anal endosonography.

BACKGROUND: Anal canal squeeze pressure is assumed to be due to external sphincter contraction, but the contribution of other muscles has not been explored. METHODS: Ten male and ten nulliparous female asymptomatic subjects had three-dimensional anal endosonography and manometry. Incremental squeeze pressures at 0. 5-cm intervals, expressed as a percentage of the maximum pressure recorded anywhere in the canal, were related to the following anatomical levels: puborectalis, overlap between external anal sphincter (EAS) and puborectalis, external and internal anal sphincters, and external anal sphincter only. Levels were determined by coronal and sagittal endosonographic reconstructions. RESULTS: Puborectalis was the same length in men and women (median 23.9 versus 27.1 mm) but represented a greater proportion of the anal canal in women (45 versus 61 per cent; P = 0.02). At the level of puborectalis alone, the pressure generated as a proportion of maximum anal canal pressure was 71 (range 32-100) per cent in men and 62 (range 32-100) per cent in women. At the level of the EAS alone, the pressure was 60 (4-98) per cent in men and 82 (41-100) per cent in women; where the external sphincter was overlapped by puborectalis, the pressure was 98 (60-100) per cent in men and 75 (47-100) per cent in women. CONCLUSION: Maximal anal canal squeeze pressure is found where the puborectalis overlaps the EAS. This segment represents a significant proportion of anal canal length in women.

Use of vector volume manometry and endoanal magnetic resonance imaging in the adult female for assessment of anal sphincter dysfunction.

PURPOSE: This study compared conventional water-perfused and vector volume anal manometry in female patients with neurogenic fecal incontinence and chronic anal fissure and in healthy female volunteers. We used endoanal magnetic resonance (MR) imaging to measure internal and external sphincter lengths and thicknesses and contrasted these with the manometric findings in the different anorectal conditions. METHODS: One hundred thirty-three female subjects were studied over an eight-month period, including 33 control volunteers, 83 patients with neurogenic fecal incontinence, and 17 patients with chronic anal fissure. Conventional manometry was contrasted with automated vector volume-derived parameters. Endoanal magnetic resonance images were obtained using a previously described internal coil with a 0.5 T Asset scanner measuring quadrantal internal sphincter thickness and averaged coronal internal and external sphincter lengths. RESULTS: There was a statistically significant relationship between parameters measured by conventional manometry and those variables derived from vector volume manometry at rest and squeeze. There was no difference in sectorial vector-derived pressures within any anorectal condition and no correlation between quadrantal internal sphincter thickness measurements and sectorial pressures at rest. Patients with chronic anal fissure and neurogenic fecal incontinence had constitutionally shorter superficial and subcutaneous external sphincters than healthy control subjects (P < 0.001). CONCLUSIONS: There is no association between manometric findings and morphologic sphincter measurement; however, the shorter distal external sphincter in patients with fissure might render the lower anal canal relatively unsupported after internal sphincterotomy in the female patient.

Three-dimensional endoanal sonography in assessing anal canal injury.

BACKGROUND: Instrument design limits endosonography of the anal canal to the axial plane, with no capability for longitudinal imaging or measurement. Using three-dimensional reconstructions, the relationship between the radial and linear extent of an anal sphincter tear has been explored, and sex differences in anal canal and sphincter length have been established. METHODS: Three-dimensional reconstructions were performed in 20 controls and 24 patients with faecal incontinence found to have 25 external and five internal sphincter defects. The radial and linear extent of any sphincter tear was measured. In controls the length of the sphincters was compared with the total anal canal length, and the maximum and mean internal sphincter thickness was compared. RESULTS: The radial angle of an internal or external sphincter defect was significantly related to its length (R2 = 96.8 per cent and R2 = 84.4 per cent respectively; both P < 0.001). The anal canal was longer in men than in women (mean(s.d.) 32.6(5.3) versus 25.1(3.4) mm; P < 0.001). The internal anal sphincter was also longer in men (25.6(6.3) versus 19.8(4.0) mm; P < 0.02), but the mean internal sphincter length as a percentage of total anal canal length did not differ (78.3 versus 78.7 per cent; P not significant). The anterior external anal sphincter was longer in men than in women (32.6(5.3) versus 15.3(2.8) mm; P < 0.001), and formed a greater percentage of total anal canal length (100 versus 62.9 per cent; P < 0.001). CONCLUSION: Multiplanar imaging has revealed a direct relationship between the length of a sphincter tear and its radial extent as shown on axial scanning. Marked sex differences in sphincter configuration have been demonstrated. In women the shorter anterior sphincter length highlights the risk of complete sphincter disruption with extensive tears.

Intraobserver and interobserver agreement in anal endosonography.

BACKGROUND: The aim of this study was to determine intraobserver and interobserver agreement for sonographic measurements of anal canal structures using anal endosonography (AES), and to determine interobserver agreement for the diagnosis of anal sphincter disruption. METHODS: Fifty-one consecutive patients referred for AES for the investigation of possible sphincter abnormality were examined. Studies were reviewed by two observers who measured anal canal structures at defined levels and locations, and recorded an opinion on sphincter integrity. Repeated measurements made by each observer were compared to determine intraobserver agreement, and measurements and diagnoses were compared between observers to determine interobserver agreement. RESULTS: Intraobserver agreement was better than interobserver agreement for measurements of anal canal structures. Interobserver limits of agreement for external sphincter measurements spanned 5 mm, whereas those for the internal sphincter spanned 1.5 mm. Interobserver agreement for diagnosis of sphincter disruption and internal sphincter echogenicity was very good (kappa = 0.80 and 0.74 respectively). CONCLUSION: The limits of agreement for intraobserver and interobserver measurements of anal canal structures on AES have been defined. Interobserver assessment of sphincter disruption is very good.

Parameters of the rectoanal inhibitory reflex in patients with idiopathic fecal incontinence and chronic constipation.

PURPOSE: The rectoanal inhibitory reflex is a response of the internal anal sphincter to rectal distention, reflecting the functional nature of the anal sampling mechanism of rectal discrimination. The aim of this study was to assess the parameters of the rectoanal inhibitory reflex in healthy volunteers and incontinent and symptomatically constipated patients. METHODS: The rectoanal inhibitory reflex was recorded in 42 patients using reproducible threshold volumes. Excitatory and inhibitory latencies, maximum excitatory and inhibitory pressures, amplitude, and slope of inhibition, slope and time of pressure recovery, and area under the inhibitory curve were estimated. Pudendal nerve terminal motor latency and endoanal magnetic resonance imaging were performed in all incontinent patients. RESULTS: Significant linear trends were found for most parameters at each sphincter level when analyzed. Recovery time and area under the inhibitory curve differed between the sphincter levels and patient groups, with the most rapid recovery occurring in the distal sphincter of incontinent patients (P < 0.001). These pressure findings were not accounted for by differences in excitation between patient groups. CONCLUSION: A coordinated response by the internal anal sphincter to rectal distention with recovery of anal pressure from the distal to the proximal sphincter is suggested. Continence may rely on the character of internal anal sphincter inhibition, and recovery and preoperative assessment of rectoanal inhibitory reflex parameters may be important for predicting functional result following low anastomosis.

High resolution magnetic resonance imaging of the anal sphincter using a dedicated endoanal coil. Comparison of magnetic resonance imaging with surgical findings.

PURPOSE: To obtain high resolution images of the anal sphincter and adjacent anorectum using an endoanal coil in patients with sepsis, trauma, and low rectal tumors and to compare imaging appearances with findings at time of surgery. PATIENTS AND METHODS: A cylindrical saddle geometry coil (diameter, 9 mm; length, 75 mm) was used to examine 30 patients (mean age, 53.6 years). Pathologies included perianal sepsis (10 patients), obstetric trauma (7 patients), and low rectal tumors (13 patients). Imaging was performed on an 0.5-T Picker Asset or 1.0-T Picker HPQ Vista (Picker International, Highland Heights, OH). T1 and T2 weighted and short inversion time inversion recovery transverse images and T1 weighted coronal images were obtained. Intravenous gadopentetate dimeglumine (0.1 mmol/kg) was given to all patients with suspected infection and neoplasms. RESULTS: Abscesses and fistulas identified using magnetic resonance imaging (MRI) in patients with perianal sepsis were confirmed at surgery in all cases; site of fistulous internal opening into the anal canal was correctly identified in 80 percent of cases. Extent of sphincter tear was correctly assessed on endoanal MRI in all patients with obstetric trauma when compared with surgical findings. Tumor invasion of anal sphincter was seen in 38.5 percent of low rectal carcinomas. CONCLUSIONS: MRI with an endoanal coil provides detailed images of the site and extent of anal fistulas, sphincter tears, and local tumors and is of considerable value in preoperative assessment.

MRI of the anal sphincter.

OBJECTIVE: The anal sphincter was imaged with MR using an internal coil to demonstrate its anatomy, contrast enhancement patterns, and appearance in disease. MATERIALS AND METHODS: A cylindrical saddle geometry coil was placed in the anal canal. Sixteen volunteers and 18 patients were examined. Imaging was performed on a 0.5 T Picker Asset MRI scanner in all the volunteers and nine patients and on a 1.0 T Picker HPQ Vista in nine patients. Then T1- and T2-weighted SE, T1-weighted GE and STIR images transverse to the sphincter, and T1-weighted SE images parallel to the sphincter in the coronal oblique plane were obtained. Intravenous gadopentetate dimeglumine (0.1 mmol/kg) was given to 2 normal subjects for dynamic studies and 10 patients for conventional postcontrast imaging. RESULTS: The coils were easy to insert and well tolerated and provided high spatial resolution. The internal sphincter had a higher signal intensity than the external sphincter on all sequences but particularly on STIR images. Brisk contrast enhancement of the internal sphincter was seen. Sphincteric abscesses and fistulous tracks were identified in three patients and confirmed at surgery. Sphincter defects were seen in three patients with past obstetric trauma, and these were also confirmed at surgery. Sphincter atrophy was seen in three patients with idiopathic fecal soiling. CONCLUSION: MRI of the anal sphincter with an internal coil provides excellent visualization of normal anatomy and may be of considerable value in diagnosis.

High resolution magnetic resonance imaging of the anal sphincter using an internal coil.

An internal receiver coil was used to obtain high resolution transverse and oblique coronal magnetic resonance images of the anal sphincter in five normal volunteers and five patients. The internal sphincter had a high signal intensity on T1 weighted, T2 weighted, and STIR sequences whereas the conjoined longitudinal muscle and external sphincter had a low signal intensity. The internal sphincter (but not the external sphincter) showed contrast enhancement after administration of intravenous gadopentetate dimeglumine. The oblique coronal plane was particularly useful for showing the thickness and the relations of the external sphincter. Sphincteric abscesses as well as muscle defects, hypertrophy, and atrophy were clearly shown. The coil was well tolerated by most subjects. It has considerable potential for improving the diagnosis of anorectal disease.

Surveillance policy for early detection of failing arteriovenous fistulae for haemodialysis.

We have developed a programme of surveillance for arteriovenous fistulae. Indications for investigation were a reduction of thrill or pulsation on the fistula, decreasing flow (< 200 ml/min) and/or increased venous return pressure (> 150 mmHg.) when on haemodialysis. Between March 1992 and February 1993 we performed intravenous digital subtraction fistulograms in 17 patients. These investigations demonstrated vein stenosis in 11 patients, nine with primary arteriovenous fistulae and in two with secondary access. There was disease of the arterial inflow in one, and no evidence of anatomical problems in the remaining five. As a result revision surgery was performed in 10 cases and percutaneous transluminal angioplasty in the remaining two cases. Five patients underwent dialysis the following day on the same site, avoiding temporary access. Sixteen patients (94%) are still using the same site for haemodialysis at mean follow-up time of 6.1 months (range 2-12 months) and one failed subsequently. Close surveillance of arteriovenous fistulae leads to detection of stenosis prior to occlusion and intervention increases patency, preserves alternative access sites, and prevents central venous cannulation for temporary access.

Cholesterolosis in patients with chronic acalculous biliary pain.

The outcome of patients with cholesterolosis was compared with that of those with chronic cholecystitis operated on for chronic acalculous biliary pain. A total of 55 patients with acalculous biliary pain with a median symptom duration of 24 (range 6-120) months were investigated by dynamic cholescintigraphy and followed for a median of 24 (range 12-60) months. Thirty-five patients underwent cholecystectomy, of whom 22 had a low gallbladder ejection fraction (under 35 per cent), with symptomatic improvement in 21 of these (P < 0.01). All four patients with a normal ejection fraction (35-50 per cent) improved after cholecystectomy but only four of nine with a high ejection fraction (over 50 per cent) did so. Results of histological examination were available in 32 patients and revealed cholesterolosis in 20. A low ejection fraction was found in 16 patients with cholesterolosis, of whom 15 showed symptomatic improvement after cholecystectomy; the other four patients had a high fraction and all improved after cholecystectomy. Overall, symptoms in 19 of 20 patients with cholesterolosis improved after cholecystectomy compared with only seven of 12 with chronic cholecystitis (P = 0.03).