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T1341 Sustained Improvement in Anal Canal Function Following External Anal Sphincter Muscle Plication
Long-term Effect of EAS Plication on Anal canal Pressure (mmHg) with maximal Electrical stimulus (6 mA). Data are shown as mean± SE.
T1342 Fecal Incontinence in the Long Term After Conformal 3D Radiotherapy of the Prostate Holger Seidl, Felix Gundling, Anne-Cathrin von der Au, Sabrina T. Astner, Hans Geinitz, Christian Pesenti INTRODUCTION: Fecal incontinence is reported by 29-70% of patients with prostate cancer 6-36 months after curative radiotherapy. Data about the long-term course are sparse. AIMS: To evaluate prevalence, severity and mechanisms of fecal incontinence in the longterm after radiotherapy and its effect on quality of life (QOL). METHODS: Out of 249 pts with radiotherapy for prostate cancer (1994-2000), 43,7% complained about fecal incontinence (mostly mild) during a first survey after a median of 46 months. 105 of these pts with fecal incontinence could be reevaluated 92 months (median) after therapy. We determined prevalence of fecal incontinence, severity (Parks classification, Wexner score), rectal toxicity score (rectal complaints after radiotherapy), bother score (restrictions after radiotherapy), EORTC C30 (global QOL), EORTC PR25 (QOL of pts with prostate cancer) und Rockwood score (QOL of pts with fecal incontinence). Additionally, 17 pts (median 7.1 ys after radiotherapy) with fecal incontinence underwent (Wiener-Score: severity of radiation proctitis) sphincter-EMG, endosonography and anorectal manometry. RESULTS: 53,3% of the pts still suffered from fecal incontinence. About 1/3 each were incontinent for gas, liquids, and solids (Parks 1/2/3, 30.4/35.7/33.9%). Parks classification were significantly related to the Wexner score, rectal toxicity score, bother score, EORTC C30 and EORTC PR25. The global QOL (EORTC C30) was significantly reduced in pts with fecal incontinence compared to an age- and sex-matched healthy cohort (p<0.001, fig. 1). A radiation proctitis (all mild) was seen in 75% of the 17 pts with further examination. Causes of incontinence are displayed in table 1/2. More than one mechanism for fecal incontinence was found in 62,5% of the patients CONCLUSION: Fecal incontinence after radiotherapy for prostate cancer persists in about half of the patients in the long-term course with mild to moderate severity in 2/3 of the patients. QOL is decreased in these patients with a strong relationship between the severity of fecal incontinence and the magnitude of depression of QOL. Most of the patients with fecal incontinence after radiotherapy suffer from a reduced rectal compliance. However, in 2/3 of the patients further mechanisms are involved. Pathophysiological mechanisms of radiation induced fecal incontinence
T1340 Inhibition of 3-Hydroxy-3-Methylglutaryl Coenzyme a (HMG-CoA) Reductase Decreases Spontaneous Smooth Muscle Tone of the Internal Anal Sphincter (IAS) via RHOA Prenylation Satish C. Rattan Background & Aims: RhoA prenylation is an important step in the translocation of RhoA in the smooth muscle tone. Statins inhibit downstream post-translational prenylation of RhoA by HMG-CoA reductase inhibition. The relationship between changes in RhoA prenylation following statins and the IAS tone has not been investigated. In these studies, we used simvastatin as a typical statin. Methods: Present studies determined RhoA prenylation and its association with the basal tone in the IAS before and after HMG-CoA reductase inhibitor simvastatin pre-treatment (24 h; 0.1 to 10 μM). We also determined the possible reversal of RhoA prenylation and the IAS tone, via geranylgeranyltransferase (GTase I) substrate geranylgeranyl pyrophosphate (GGPP). (GGTase I is critical rate limiting step in the RhoA prenylation from GGPP). We performed Western blot analyses of the cytosolic vs. membrane fractions of the smooth muscles, to determine the effects of HMG-CoA reductase inhibition on RhoA prenylation as well as the cellular distribution of RhoA/ROCK. Some studies were also performed in the freshly isolated smooth muscle cells of the IAS vs. the RSM. Results: Simvastatin produced significant and concentration-dependent decrease in the IAS tone and relaxation of the SMC, associated with the corresponding decrease in the prenylation of RhoA (*; p < 0.05; n = 4). In addition, simvastatin caused rightward shift in the concentrationresponse curves showing increase in the IAS tone by thromboxane A2 analog U-46619. (The inhibitory effect of simvastatin was agonist-specific because bethanechol-induced increase in the IAS tone was not affected.) Different inhibitory effects of simvastatin were completely reversed by GGPP (*; p < 0.05; n = 4). In the basal state, in the tonic IAS smooth mucle (in contrast with the phasic rectal smooth muscle), RhoA/ROCK were found to be concentrated primarily in the membranous fractions as compared with the cytosolic fractions. The decrease in the IAS tone caused by simvastatin was associated with the reversal of the trend not only of prenylated RhoA but also that of RhoA/ROCK, in a concentration-dependent manner. Conclusions: Decrease in the IAS smooth muscle tone by HMG-CoA reductase inhibitor simvastatin is mediated via the downstream blockade of RhoA prenylation. Studies further support the concept that RhoA prenylation is critical for the translocation of RhoA to the smooth muscle cell membrane of the IAS. From these data we conclude that the effects of HMG-CoA inhibitors statins may go beyond inhibition of cholesterol biosynthesis, that includes modulation of the basal IAS tone.
Pathological results of anorectal manometry
T1343 Ultrasound Evaluation of the Posterior Compartment of the Female Pelvic Floor: Trans-Labial Assessment of Normal Anatomy and Pathologic Conditions Luca M. Sconfienza, Edoardo Savarino, Francesca Lacelli, Giovanni Serafini, Vincenzo Savarino
T1341
Introduction: The ultrasound evaluation of the posterior compartment of the female pelvic floor usually represents a diagnostic challenge for the complexity of its anatomy. Advances in ultrasound technology allowed to build new volumetric probes capable to provide relevant information otherwise impossible to obtain without a trans-rectal approach. Aim: To demonstrate how volumetric trans-labial ultrasound is able to depict normal anatomy of the posterior compartment of the pelvic floor in a group of healthy volunteers and the role of such technology in the diagnosis of pathologic conditions of the rectum-anus. Methods: Study group included 24 nulliparous volunteers (mean age 26±5.1 years), who referred for conventional transvaginal ultrasound examination to assess different ovarian conditions and who never reported any symptoms possibly related to the posterior pelvic compartment, and 22 patients (mean age 43±7.3 years) affected by different ano-rectal conditions (obstructed defecation syndrome, n=6; ano-rectal fistula, n=4; fecal/gas incontinence, n=10). All subjects were imaged with a trans-labial approach by means of an automatic volumetric end-fire probe (8-4MHz) and an high-end ultrasound equipment (iU22, Philips NV, The Netherlands). Data were stored and later reformatted according to axial and oblique scan plans. Results: In all volunteers (100%), volumetric ultrasound imaging demonstrated the normal anatomy of the smooth and striated sphincters of the anus. All musculotendineous components of the elevator of the anus were clearly detected in 22/24 patients (92%). No ano-rectal affections were found in this group. In patients affected by obstructed defecation syndrome, 5 anterior rectocele and 1 elytrocele were found. In patients affected by ano-rectal fistula, the course and the length of the lesion were clearly demonstrated. Lesions of the sphincters of different degrees could be demonstrated in all patients affected by incontinence. Conclusions: Translabial ultrasound volumetric imaging is able to provide a precise axial anatomic evaluation of the posterior compartment of the pelvic floor and of the sphincters of the anus, as well as being an effective diagnostic tool in the diagnosis of pathologic conditions of that region. Formerly, this evaluation was only possible with a trans-rectal approach that had the double disadvantage both of being discomfortable for the patients and to induce relevant distortions of the anatomy during the examination.
Sustained Improvement in Anal Canal Function Following External Anal Sphincter Muscle Plication Mahadevan R. Rajasekaran, Yanfen Jiang, Amir Motamedi, Valmik Bhargava, Ravinder K. Mittal Background: We recently found that anal canal function and external anal sphincter (EAS) contraction can be enhanced by surgically adjusting the EAS muscle sarcomere length. Our results show that a 20% length of EAS muscle plication results in significant increase in anal canal pressure and EAS muscle tension without affecting its passive tension characteristics. The durability of the beneficial effect of EAS muscle plication on the anal canal function is not known. Aims: The goal of our study was to determine the long-term effects of optimal EAS plication on the anal canal pressure. Methods: Female rabbits (n=8) were anesthetized and either sham (n=2) or EAS plication (n=6) surgery was performed. The circumference of the anal canal was measured with a caliper. An incision was made on the skin of the anal canal to expose the EAS muscle and sutures (4.0-gauge polypropylene) were placed at 2 points, at a distance of 20% of the circumferential length of the anal canal. The 2 ends of the sutures were tied together (EAS plication) and the skin incision was closed. Anal canal pressures were recorded using a 3 mm sleeve sensor catheter, before and after surgery, at two week intervals. Effect of EAS plication on the anal canal pressure during electrical (1-6mA) stimulation of the EAS (active contraction) was recorded. Fecal pellet diameter was measured before and after surgery. Results: Electrical stimulation of the EAS muscle result in a stimulus dependent increase in the anal canal pressure. With 20% plication, there was a 60-70% increase in the anal canal pressure (during maximum electrical stimulus), as compared to no plication (Table). This beneficial effect was durable for up to 10 weeks (tested so far) post-plication. The fecal pellet size was not different between the sham and plicated animals. Conclusions: Our results suggest that the beneficial effect of 20% EAS plication on the anal canal function is durable and the EAS plication has no untoward effect on anal canal opening function up to 10 weeks post-plication.
S-541
AGA Abstracts
AGA Abstracts
bilateral pelvic nerve transection and subdiaphragmatic truncal vagotomy. To evaluate the colonic transit, a catheter was inserted into the proximal colon. At the post-operative day (POD) 1, 3, and 7, 51Cr was injected into the proximal colon and the distribution of 51Cr (geometric center; GC) was calculated. A 5-HT3R antagonist (ondansetron; 1 mg/kg) was injected (sc) 15 min before the 51Cr administration. 5-HT3R expression in the mucosal layer of proximal, middle and distal colon was determined by real time RT-PCR and Western blot at POD3 and POD7. Results: Parasympathetic denervation caused a significant delay of colonic transit (GC=4.36±0.64, n=6, P<0.01) at POD1, compared to sham groups (GC= 6.31±0.62, n=8). Delayed transit was gradually restored at POD3 (GC=5.19±0.49, n=8, P<0.05) and POD7 (GC=5.99±0.58, n=8, P>0.05) after the denervation. Restored GC was antagonized by the administration of a 5-HT3R antagonist (GC=4.16±0.30, n=6, P<0.01) at POD7. At POD 3, 5-HT3R mRNA and protein expression in the mucosal layer was significantly increased, compared to that of sham groups. At POD7, there was no significant difference in 5-HT3R mRNA expression between the denervation and sham groups, whereas the 5-HT3R protein expression was still significantly elevated after the denervation. Conclusions: Parasympathetic denervation significantly delayed colonic transit in rats. It appears that a compensatory mechanism was developed to normalize colonic transit over time. Upregulation of 5-HT3R expression in the mucosal layer is involved in mediating the adaptation mechanism to restore the delayed transit after the parasympathetic denervation in rats.
T1342 Fecal Incontinence in the Long Term After Conformal 3D Radiotherapy of the Prostate Holger Seidl, Felix Gundling, Anne-Cathrin von der Au, Sabrina T. Astner, Hans Geinitz, Christian Pesenti INTRODUCTION: Fecal incontinence is reported by 29-70% of patients with prostate cancer 6-36 months after curative radiotherapy. Data about the long-term course are sparse. AIMS: To evaluate prevalence, severity and mechanisms of fecal incontinence in the longterm after radiotherapy and its effect on quality of life (QOL). METHODS: Out of 249 pts with radiotherapy for prostate cancer (1994-2000), 43,7% complained about fecal incontinence (mostly mild) during a first survey after a median of 46 months. 105 of these pts with fecal incontinence could be reevaluated 92 months (median) after therapy. We determined prevalence of fecal incontinence, severity (Parks classification, Wexner score), rectal toxicity score (rectal complaints after radiotherapy), bother score (restrictions after radiotherapy), EORTC C30 (global QOL), EORTC PR25 (QOL of pts with prostate cancer) und Rockwood score (QOL of pts with fecal incontinence). Additionally, 17 pts (median 7.1 ys after radiotherapy) with fecal incontinence underwent (Wiener-Score: severity of radiation proctitis) sphincter-EMG, endosonography and anorectal manometry. RESULTS: 53,3% of the pts still suffered from fecal incontinence. About 1/3 each were incontinent for gas, liquids, and solids (Parks 1/2/3, 30.4/35.7/33.9%). Parks classification were significantly related to the Wexner score, rectal toxicity score, bother score, EORTC C30 and EORTC PR25. The global QOL (EORTC C30) was significantly reduced in pts with fecal incontinence compared to an age- and sex-matched healthy cohort (p<0.001, fig. 1). A radiation proctitis (all mild) was seen in 75% of the 17 pts with further examination. Causes of incontinence are displayed in table 1/2. More than one mechanism for fecal incontinence was found in 62,5% of the patients CONCLUSION: Fecal incontinence after radiotherapy for prostate cancer persists in about half of the patients in the long-term course with mild to moderate severity in 2/3 of the patients. QOL is decreased in these patients with a strong relationship between the severity of fecal incontinence and the magnitude of depression of QOL. Most of the patients with fecal incontinence after radiotherapy suffer from a reduced rectal compliance. However, in 2/3 of the patients further mechanisms are involved. Pathophysiological mechanisms of radiation induced fecal incontinence
T1340 Inhibition of 3-Hydroxy-3-Methylglutaryl Coenzyme a (HMG-CoA) Reductase Decreases Spontaneous Smooth Muscle Tone of the Internal Anal Sphincter (IAS) via RHOA Prenylation Satish C. Rattan Background & Aims: RhoA prenylation is an important step in the translocation of RhoA in the smooth muscle tone. Statins inhibit downstream post-translational prenylation of RhoA by HMG-CoA reductase inhibition. The relationship between changes in RhoA prenylation following statins and the IAS tone has not been investigated. In these studies, we used simvastatin as a typical statin. Methods: Present studies determined RhoA prenylation and its association with the basal tone in the IAS before and after HMG-CoA reductase inhibitor simvastatin pre-treatment (24 h; 0.1 to 10 μM). We also determined the possible reversal of RhoA prenylation and the IAS tone, via geranylgeranyltransferase (GTase I) substrate geranylgeranyl pyrophosphate (GGPP). (GGTase I is critical rate limiting step in the RhoA prenylation from GGPP). We performed Western blot analyses of the cytosolic vs. membrane fractions of the smooth muscles, to determine the effects of HMG-CoA reductase inhibition on RhoA prenylation as well as the cellular distribution of RhoA/ROCK. Some studies were also performed in the freshly isolated smooth muscle cells of the IAS vs. the RSM. Results: Simvastatin produced significant and concentration-dependent decrease in the IAS tone and relaxation of the SMC, associated with the corresponding decrease in the prenylation of RhoA (*; p < 0.05; n = 4). In addition, simvastatin caused rightward shift in the concentrationresponse curves showing increase in the IAS tone by thromboxane A2 analog U-46619. (The inhibitory effect of simvastatin was agonist-specific because bethanechol-induced increase in the IAS tone was not affected.) Different inhibitory effects of simvastatin were completely reversed by GGPP (*; p < 0.05; n = 4). In the basal state, in the tonic IAS smooth mucle (in contrast with the phasic rectal smooth muscle), RhoA/ROCK were found to be concentrated primarily in the membranous fractions as compared with the cytosolic fractions. The decrease in the IAS tone caused by simvastatin was associated with the reversal of the trend not only of prenylated RhoA but also that of RhoA/ROCK, in a concentration-dependent manner. Conclusions: Decrease in the IAS smooth muscle tone by HMG-CoA reductase inhibitor simvastatin is mediated via the downstream blockade of RhoA prenylation. Studies further support the concept that RhoA prenylation is critical for the translocation of RhoA to the smooth muscle cell membrane of the IAS. From these data we conclude that the effects of HMG-CoA inhibitors statins may go beyond inhibition of cholesterol biosynthesis, that includes modulation of the basal IAS tone.
Pathological results of anorectal manometry
T1343 Ultrasound Evaluation of the Posterior Compartment of the Female Pelvic Floor: Trans-Labial Assessment of Normal Anatomy and Pathologic Conditions Luca M. Sconfienza, Edoardo Savarino, Francesca Lacelli, Giovanni Serafini, Vincenzo Savarino
T1341
Introduction: The ultrasound evaluation of the posterior compartment of the female pelvic floor usually represents a diagnostic challenge for the complexity of its anatomy. Advances in ultrasound technology allowed to build new volumetric probes capable to provide relevant information otherwise impossible to obtain without a trans-rectal approach. Aim: To demonstrate how volumetric trans-labial ultrasound is able to depict normal anatomy of the posterior compartment of the pelvic floor in a group of healthy volunteers and the role of such technology in the diagnosis of pathologic conditions of the rectum-anus. Methods: Study group included 24 nulliparous volunteers (mean age 26±5.1 years), who referred for conventional transvaginal ultrasound examination to assess different ovarian conditions and who never reported any symptoms possibly related to the posterior pelvic compartment, and 22 patients (mean age 43±7.3 years) affected by different ano-rectal conditions (obstructed defecation syndrome, n=6; ano-rectal fistula, n=4; fecal/gas incontinence, n=10). All subjects were imaged with a trans-labial approach by means of an automatic volumetric end-fire probe (8-4MHz) and an high-end ultrasound equipment (iU22, Philips NV, The Netherlands). Data were stored and later reformatted according to axial and oblique scan plans. Results: In all volunteers (100%), volumetric ultrasound imaging demonstrated the normal anatomy of the smooth and striated sphincters of the anus. All musculotendineous components of the elevator of the anus were clearly detected in 22/24 patients (92%). No ano-rectal affections were found in this group. In patients affected by obstructed defecation syndrome, 5 anterior rectocele and 1 elytrocele were found. In patients affected by ano-rectal fistula, the course and the length of the lesion were clearly demonstrated. Lesions of the sphincters of different degrees could be demonstrated in all patients affected by incontinence. Conclusions: Translabial ultrasound volumetric imaging is able to provide a precise axial anatomic evaluation of the posterior compartment of the pelvic floor and of the sphincters of the anus, as well as being an effective diagnostic tool in the diagnosis of pathologic conditions of that region. Formerly, this evaluation was only possible with a trans-rectal approach that had the double disadvantage both of being discomfortable for the patients and to induce relevant distortions of the anatomy during the examination.
Sustained Improvement in Anal Canal Function Following External Anal Sphincter Muscle Plication Mahadevan R. Rajasekaran, Yanfen Jiang, Amir Motamedi, Valmik Bhargava, Ravinder K. Mittal Background: We recently found that anal canal function and external anal sphincter (EAS) contraction can be enhanced by surgically adjusting the EAS muscle sarcomere length. Our results show that a 20% length of EAS muscle plication results in significant increase in anal canal pressure and EAS muscle tension without affecting its passive tension characteristics. The durability of the beneficial effect of EAS muscle plication on the anal canal function is not known. Aims: The goal of our study was to determine the long-term effects of optimal EAS plication on the anal canal pressure. Methods: Female rabbits (n=8) were anesthetized and either sham (n=2) or EAS plication (n=6) surgery was performed. The circumference of the anal canal was measured with a caliper. An incision was made on the skin of the anal canal to expose the EAS muscle and sutures (4.0-gauge polypropylene) were placed at 2 points, at a distance of 20% of the circumferential length of the anal canal. The 2 ends of the sutures were tied together (EAS plication) and the skin incision was closed. Anal canal pressures were recorded using a 3 mm sleeve sensor catheter, before and after surgery, at two week intervals. Effect of EAS plication on the anal canal pressure during electrical (1-6mA) stimulation of the EAS (active contraction) was recorded. Fecal pellet diameter was measured before and after surgery. Results: Electrical stimulation of the EAS muscle result in a stimulus dependent increase in the anal canal pressure. With 20% plication, there was a 60-70% increase in the anal canal pressure (during maximum electrical stimulus), as compared to no plication (Table). This beneficial effect was durable for up to 10 weeks (tested so far) post-plication. The fecal pellet size was not different between the sham and plicated animals. Conclusions: Our results suggest that the beneficial effect of 20% EAS plication on the anal canal function is durable and the EAS plication has no untoward effect on anal canal opening function up to 10 weeks post-plication.
S-541
AGA Abstracts
AGA Abstracts
bilateral pelvic nerve transection and subdiaphragmatic truncal vagotomy. To evaluate the colonic transit, a catheter was inserted into the proximal colon. At the post-operative day (POD) 1, 3, and 7, 51Cr was injected into the proximal colon and the distribution of 51Cr (geometric center; GC) was calculated. A 5-HT3R antagonist (ondansetron; 1 mg/kg) was injected (sc) 15 min before the 51Cr administration. 5-HT3R expression in the mucosal layer of proximal, middle and distal colon was determined by real time RT-PCR and Western blot at POD3 and POD7. Results: Parasympathetic denervation caused a significant delay of colonic transit (GC=4.36±0.64, n=6, P<0.01) at POD1, compared to sham groups (GC= 6.31±0.62, n=8). Delayed transit was gradually restored at POD3 (GC=5.19±0.49, n=8, P<0.05) and POD7 (GC=5.99±0.58, n=8, P>0.05) after the denervation. Restored GC was antagonized by the administration of a 5-HT3R antagonist (GC=4.16±0.30, n=6, P<0.01) at POD7. At POD 3, 5-HT3R mRNA and protein expression in the mucosal layer was significantly increased, compared to that of sham groups. At POD7, there was no significant difference in 5-HT3R mRNA expression between the denervation and sham groups, whereas the 5-HT3R protein expression was still significantly elevated after the denervation. Conclusions: Parasympathetic denervation significantly delayed colonic transit in rats. It appears that a compensatory mechanism was developed to normalize colonic transit over time. Upregulation of 5-HT3R expression in the mucosal layer is involved in mediating the adaptation mechanism to restore the delayed transit after the parasympathetic denervation in rats.