Evoked pressure curves from the external anal sphincter following transcranial magnetic stimulation in healthy volunteers and patients with faecal incontinence.

AIM: The hypothesis was tested that evoked pressure curves (EPCs) after transcranial magnetic stimulation (TMS) would provide additional neuropathophysiological information on the descending pathways to the external anal sphincter (EAS) in patients with faecal incontinence (FI). METHOD: Twenty-five healthy subjects and 69 patients with FI were investigated. TMS was applied to the vertex, and EPCs were recorded with a probe placed through the EAS. TMS was performed with the EAS at rest and during contraction (facilitated responses). At least three responses were recorded for each modality. Clinical data and anorectal manometric, electrophysiological perineal and transanal ultrasound recordings were compared with respect to the EPC results. RESULTS: There was no statistically significant difference between the EPCs of healthy subjects and FI patients. Twenty-three per cent of the FI patients had abnormal EPC latencies, with significantly lower voluntary contraction amplitudes (P = 0.03) and significantly higher rectal sensation (P = 0.04) than the other group. We found no significant difference between FI patients with and without abnormal EPC latencies in terms of clinical characteristics and electrophysiological and endoanal ultrasound parameters. There was no difference in the identified causes of the FI between the two groups. CONCLUSION: As abnormal EPC latencies were found in 23% of FI patients with no known central neurological disease, abnormal EPC latencies might reveal undetected lesions of descending pathways in patients with FI.

Definitive chemoradiotherapy in patients with esophageal adenocarcinoma: an alternative to surgery?

BACKGROUND AND OBJECTIVES: Definitive chemoradiotherapy (CRT) is considered curative intent treatment for locally advanced esophageal squamous cell carcinoma. Data concerning the usefulness of definitive CRT in patients with esophageal adenocarcinoma (ADC) are lacking. The aim of the study was to compare the results of definitive CRT versus surgery in patients with an ADC. METHODS: All consecutive patients with a non-metastatic ADC treated between 1994 and 2008 were retrospectively assessed. Patients were divided into two groups: surgery group (±pre-operative treatment) versus definitive CRT group. RESULTS: In surgery and definitive CRT groups, 67 and 79 patients were evaluated, respectively. A complete resection was achieved in 92.5% of patients in surgery group and a clinical complete response was observed in 49.4% of patients in definitive CRT group. Overall survival was 36.2 ± 2.0 months in surgery group versus 16.5 ± 0.8 months in definitive CRT group (P = 0.02). The predictive factors of survival were age (P < 0.01), stage (P = 0.04), WHO performance status (P < 0.01), initial weight loss (P < 0.01), and the treatment group (P < 0.01). CONCLUSIONS: The results of the study do not support definitive CRT as an alternative to surgery in esophageal ADC treatment. Definitive CRT should be reserved for patients with a major operative risk.

Botulinum A toxin as a treatment for overactive rectum with associated faecal incontinence.

AIM: Rectal hypercontractility can lead to faecal incontinence (FI). Botulinum toxin (BT) has been used successfully for the treatment of bladder overactivity. This study aimed to evaluate the therapeutic value of intrarectal injections of BT in inhibiting colorectal contractions and relieving FI in patients suffering from FI as a result of overactive rectal contractions. METHOD: A prospective open study was carried out in Rouen University Hospital. Six patients (four men and two women) with severe FI related to overactive rectal contractions underwent intrarectal submucosal injections of BT placed in three rows of 10, 1-ml injections (50 U/1 ml; Dysport(®)) starting 1 cm above the dentate line and repeated twice, at intervals of 5 cm proximally. The end-points included improvement in the FI score, in faecal incontinence quality of life (FIQL) and of manometric abnormality. RESULTS: All patients reported improvement in the FI score [18.2±1.1 at baseline vs 9.0±1.7 at 3 months (P=0.04)] and in FIQL. Rectal contractile activity was reduced. The frequency of contractions remained unaffected (28.1±6.6/h; P=0.46 vs baseline). High-amplitude contractions of >50 cmH(2)O were significantly decreased in all patients (16.6±3.9 vs 6.6±4.1/h; P=0.03). CONCLUSION: Patients with an 'overactive rectum' are a heterogeneous group, with varying causes of dysfunction. The dose of BT used was arbitrarily selected. Nevertheless, the study introduces a further therapeutic option in the treatment of FI caused by rectal overactivity.

Internal supravesical hernia: an unusual cause of small bowel obstruction.

Internal hernia of the supravesical fossa is an unusual cause of small bowel obstruction. We report the case of a patient without previous abdominal surgery with an acute abdominal obstruction in which laparoscopic exploration revealed a strangulated internal supravesical hernia. To help clinicians with their pre-operative diagnosis and to better understand the clinical management of this unusual internal hernia, a description of the anatomy of the supravesical fossa is included in this case report.

[Results of sacral neuromodulation on the urinary and fecal incontinence and sexuality in 20 women suffering from a double incontinence]. / Résultats de la neuromodulation des racines sacrées sur la continence et la sexualité dans une cohorte de 20 patientes ayant une double incontinence.

CONTEXT: Urinary and faecal incontinence (defining double incontinence) are common conditions, which are frequently associated and can altered sexuality. The effectiveness of the sacral nerve modulation (NMS) in the treatment of the urge urinary incontinence, faecal incontinence and double incontinence was shown. OBJECTIVE: The present article aims to determine the impact of SNM on female sexual function in twenty women suffering from a double incontinence. METHODS: All patients who received sacral neuromodulation for urge urinary and/or faecal incontinence between 2005 and 2010 and who still had the implant were included. Only 20 sexually active patients suffering from double incontinence were considered eligible. They completed a questionnaire on follow-up examinations. RESULTS: The initial indication of NMS was the urge urinary incontinence for 15 patients and the faecal incontinence for five patients. Ten patients (50%) were improved on two incontinence. All patients preserved sexual activity after the treatment of NMS. NMS improves the quality of sexual activity in 45% patients. The numbers of urinary and faecal episodes of incontinence are decreased respectively for 50% and 15% patients during sexual activity. The quality of sexual's life and orgasm score are significantly increased in the group of patients improved on the DI. CONCLUSION: This study confirms the effectiveness of NMS in the treatment of double incontinence which half patients are improved on the two incontinence. This study shows that improvement of urinary or faecal incontinence could have a positive impact on sexuality of these patients, especially for patients improved double incontinence. It is difficult to know if these results are related to its direct action on the neurological ways of sexual function or on its benefit on the continence.

A large-scale candidate gene approach identifies SNPs in SOD2 and IL13 as predictive markers of response to preoperative chemoradiation in rectal cancer.

Neoadjuvant radiochemotherapy followed by total mesorectal excision is now the standard treatment for locally advanced rectal cancer. However, tumor response to chemoradiation varies widely among individuals and cannot be determined before the final pathologic evaluation. The aim of this study was to identify germline genetic markers that could predict sensitivity or resistance to preoperative radiochemotherapy (RT-CT) in rectal cancer. We evaluated the predictive value of 128 single-nucleotide polymorphisms (SNPs) in 71 patients preoperatively treated by RT-CT. The selected SNPs were distributed over 76 genes that are involved in various cellular processes such as DNA repair, apoptosis, proliferation or immune response. The SNPs superoxide dismutase 2 (SOD2) rs4880 (P=0.005) and interleukin-13 (IL13) rs1800925 (P=0.0008) were significantly associated with tumor response to chemoradiation. These results reinforce the idea of using germline polymorphisms for personalized treatment.

How sacral nerve stimulation works in patients with faecal incontinence.

AIM: Sacral nerve stimulation (SNS) reduces incontinence episodes and improves the quality of life of patients treated for faecal incontinence. However, the exact mechanism of action of this technique remains unclear. The present article reviews the pertinent neuroanatomy and neurophysiology related to SNS and provides explanations for potential mechanisms of action. METHOD: A systematic review of the literature was performed for studies of the potential mechanisms of action of SNS, using MEDLINE, PubMed, Embase and the Cochrane Library. Articles dealing with the technique, adverse events and economic evaluations of SNS, as well as literature reviews, were excluded, except for reviews dealing with the mechanisms of action of SNS. The following inclusion criteria were used to select articles: (i) articles in English, (ii) randomized, double-blinded, sham-controlled studies, and (iii) cohort studies. Case-control studies or retrospective studies were cited only when randomized or cohort studies could not be found. RESULTS: We propose three hypotheses to explain the mechanism of action of SNS: (i) a somato-visceral reflex, (ii) a modulation of the perception of afferent information, and (iii) an increase in external anal sphincter activity. CONCLUSION: The mechanism of action of SNS in patients with faecal incontinence almost certainly depends on the modulation of spinal and/or supraspinal afferent inputs. Further research on humans and animals will be required to gain a better understanding of the mechanisms of action of SNS.

Predictive factors for successful sacral nerve stimulation in the treatment of faecal incontinence: results of trial stimulation in 200 patients.

AIM: Sacral nerve stimulation (SNS) has a place in the treatment algorithm for faecal incontinence (FI). However, after implantation, 15-30% of patients with FI fail to respond for unknown reasons. We investigated the effect of SNS on continence and quality of life (QOL) and tried to identify specific predictive factors of the success of permanent SNS in the treatment of FI. METHOD: Two hundred consecutive patients (six men; median age = 60; range 16-81) underwent permanent implantation for FI. The severity of FI was evaluated by the Cleveland Clinic Score. Quality of life was evaluated by the French version of the American Society of Colon and Rectal Surgeons (ASCRS) quality of life questionnaire (FIQL). All patients underwent a preoperative evaluation. After permanent implantation, severity and QOL scores were reevaluated after six and 12 months and then once a year. RESULTS: The severity scores were significantly reduced during SNS (P = 0.001). QOL improved in all domains. At the 6-month follow-up, the clinical outcome of the permanent implant was not affected by age, gender, duration of symptoms, QOL, main causes of FI, anorectal manometry or endoanal ultrasound results. Only loose stool consistency (P = 0.01), persistent FI even though diarrhoea was controlled by medical treatment (P = 0.004), and low stimulation intensity (P = 0.02) were associated with improved short-term outcomes. Multivariate analysis confirmed that loose stool consistency and low stimulation intensity were related to a favourable outcome. CONCLUSION: Stool consistency and low stimulation intensity have been identified as predictive factors for the short-term outcome of SNS.

Artificial anal sphincter for severe fecal incontinence implanted by a transvaginal approach: experience with 32 patients treated at one institution.

PURPOSE: Our aim was to evaluate medium-term results of transvaginal implantation of an artificial anal sphincter in a large series of patients. METHODS: Women undergoing treatment for severe fecal incontinence at Rouen University Hospital, Rouen, France, from January 2003 through December 2007 were eligible for the study if the fecal incontinence had lasted for 6 months and if they had attempted other therapies without success. All patients received implantation of an artificial anal sphincter via a transvaginal approach. Incontinence was assessed with the Cleveland Clinic Florida Fecal Incontinence Scale (Wexner score). RESULTS: A total of 32 women entered the study. Their median age was 63 (range, 26-79) years. At entry, 20 (63%) had severe destruction and scarring of the perineum, which was a contraindication for implantation via a perineal approach. Nine patients (28.1%) had previously undergone implantation of an AAS which had been removed because of complications, and 5 had had a Pickrell procedure for anal agenesia. No deaths occurred during the study. The device was removed in a total of 9 patients (28.1%): in 7 because of septic adverse events within the first 6 months after the operation, in 1 because of poor function, and in 1 for psychological reasons despite good functional results. Implantation was successful in 23 patients (71.9%), and the device remained activated for a mean follow-up of 41 (range, 18-75) months, with a mean decrease in Cleveland Clinic incontinence score from 18.4 to 6.8 (P < .0001). None of the patients complained of dyspareunia. CONCLUSIONS: The transvaginal approach for implantation of an artificial anal sphincter permits treatment of women with fecal incontinence who have severe damage and scarring of the anterior perineum. This route provides an alternative for patients whose only therapeutic option would previously have been a defunctioning stoma.

Increased expression of class III beta-tubulin in castration-resistant human prostate cancer.

BACKGROUND: Class III beta-tubulin (betaIII-tubulin) is expressed in tissues of neuronal lineage and also in several human malignancies, including non-small-cell lung carcinoma, breast and ovarian cancer. Overexpression of betaIII-tubulin in these tumours is associated with an unfavourable outcome and resistance to taxane-based therapies. At present, betaIII-tubulin expression remains largely uncharacterised in prostate cancer. METHODS: In this report, we evaluated the expression of betaIII-tubulin in 138 different human prostate tumour specimens by immunohistochemistry from patients with hormone-treated or hormone-untreated prostate cancer. betaIII-tubulin expression was also examined in various prostatic cancer cell lines including in androgen-sensitive human prostate cancer cells, LNCaP, grown in androgen-depleted medium in 2D cultures or as tumour xenografts when the host mouse was castrated. RESULTS: Whereas moderate-to-strong betaIII-tubulin expression was detected in only 3 out of 74 (4%) hormone-naive tumour specimens obtained from patients who never received hormone therapy, 6 out of 24 tumour specimens (25%) from patients treated for 3 months with neoadjuvant hormone therapy and 24 out of 40 (60%) castration-resistant tumour specimens from chronic hormone-treated patients were found to express significant levels of betaIII-tubulin. These findings were supported by in vitro and in vivo settings. CONCLUSION: Our data indicate that betaIII-tubulin expression is augmented in prostate cancer by androgen ablation and that the expression of this beta-tubulin isoform is associated with the progression of prostate cancer to the castration-resistant state, a stage largely responsible for mortality from prostate cancer.

Sacral nerve stimulation in faecal incontinence: position statement based on a collective experience.

OBJECTIVE: Since the first paper published by Matzel et al., in 1995, on the efficacy of sacral nerve stimulation (SNS) in patients with faecal incontinence, the indications, the contraindications, the stimulation technique and follow up of implanted patients have changed. The aim of this article was to provide a consensus opinion on the management of patients with faecal incontinence treated with SNS. METHOD: Recommendations were based on a critical review of the literature when available and on expert opinions in areas with insufficient evidence. RESULTS: We have reviewed the indications and contraindications, proposed an algorithm for patient management showing the place of SNS. The temporary test technique, the implantation technique, the patient follow up and the approach in case of treatment failure were discussed. CONCLUSION: We hope not only to provide a guide on patient management to clinical practitioners interested in SNS but also to harmonize our practices.

Control of pelvic symptoms in patients with rectal cancer and synchronous metastases.

OBJECTIVE: The optimal treatment strategy for rectal cancer (RC) with synchronous metastases remains an issue of debate. The aim of this study was to evaluate the impact of surgery and radiation on the control of pelvic symptoms in this setting. METHODS: Consecutive patients with RC and synchronous metastases were retrospectively assessed and divided into four treatment groups: surgical resection of rectal tumor (S); radiotherapy with/without chemotherapy followed by surgery (CRTS); chemoradiotherapy (CRT); and chemotherapy only (CT). Each group was evaluated in terms of duration of pelvic symptom-free periods (relative to overall survival). RESULTS: A total of 96 patients were evaluated: S: n=30; CRTS: n=21; CRT: n=27; and CT: n=18. After treatment, pelvic symptoms persisted in 14.7% patients (S=0%, CRTS=7.1%, CRT=31.8%, CT=25%; P=0.01). The relative pelvic symptom-free periods were 93.0% in the S group, 83.1% in the CRTS group, 53.0% in the CRT group and 53.2% in the CT group (P<0.01). On multivariate analysis, only surgical treatment correlated with a significant relative pelvic symptom-free period (P<0.01), with an adjusted hazards ratio of 2.80 [95% CI: 1.79-4.39]. CONCLUSION: Our results suggest that rectal resection was the most effective therapeutic procedure in selected patients with RC and synchronous metastases, offering the patients the longest pelvic symptom-free periods.

Combined resection of the pancreas and inferior vena cava for pancreatic metastasis from renal cell carcinoma.

Indications for pancreatic resections for metastatic disease have not yet been defined to date, and few guidelines exist for the management of these lesions. However, most authors recommend surgery as the treatment of choice for pancreatic metastasis (PM). Resection of the inferior vena cava (IVC) is rarely done during removal of peripancreatic cancer. This report presents the first case of metachronous PM from renal cell carcinoma (RCC) with IVC involvement successfully treated by en-bloc resection in a 70-year-old asymptomatic woman. The abdominal computed tomography (CT) scan showed a 4.0-cm mass in the tail and a 5.0-cm mass in the head of the pancreas with a suspected involvement of vena cava. An en-bloc total pancreatectomy was performed with excision of the involved portion of the cava vein. Histology confirmed the presence of two metastases from RCC with neoplastic infiltration of the IVC and without lymph node involvement. All surgical margins were tumor-free. At most recent follow-up 12 months after pancreatectomy, the patient has no evidence of disease. We believe that a multidisciplinary approach and careful evaluation and treatment of these patients is a mandatory component for patient selection. IVC resection should be performed only when a margin-negative resection is expected to be achieved.

[Repair of rectocele using the Stapled TransAnal Rectal Resection (STARR) technique: intermediate results from a multicenter French study]. / Traitement de la rectocèle par résection rectale transanale à la pince mécanique: résultats à moyen terme d'une étude multicentrique en France.

BACKGROUND: Stapled transanal rectal resection is a new alternative for the treatment of outlet obstruction syndrome. The aim of this study was to assess its feasibility and safety in a multicenter context. MATERIALS AND METHOD: The study had a retrospective design and included 102 patients who were operated in 5 centers. All patients complained of symptomatic outlet obstruction. Surgical technique involved a double hemi-circumferential rectal stapling according to the technique described by Longo. Mean follow-up was 17.2 months. RESULTS: The STARR procedure was done in 100 patients (2 patients had a non relaxing sphincter preventing anal dilatation). Immediate postoperative morbidity included bleeding in 4 cases (4%) and rectal stenosis in 3 cases (3%). The main postoperative medium-term complaints were urge to defecate (34%) which was regressive in most patients and de novo incontinence to flatus (9%). Nevertheless, results were considered favorable in 85% of patients. CONCLUSION: This multicenter study, reporting the results of the largest published series, suggests that the STARR technique is feasible and safe in the medium term for the treatment of rectocele. Occurrence of adverse events such as incontinence to flatus should be better evaluated by future studies with longer follow up in order to assess the actual place of STARR in the treatment of rectocele or outlet obstruction.

Sentinel node mapping in colon carcinoma: in-vivo versus ex-vivo approach.

AIM: The aim of this study was to determine if ex-vivo and in-vivo technique of lymphatic mapping for colorectal cancer (CCR) result in similar sentinel lymph node (SLN) identification and accuracy rates. METHODS: Thirty consecutive patients with 32 CCR underwent in vivo SLN mapping. After completion of the colectomy, we remapped the SLN in the operative specimens from patients who had undergone successful in vivo lymphatic mapping. RESULTS: At least one SLN was identified by in vivo approach in 32 tumours. 1.5 SLNs (1-3) and 1.8 SLNs (1-4) (p=0.24) were identified by the in vivo and the ex vivo technique, respectively. All SLNs identified by the in vivo technique were also identified by the ex vivo technique. In six cases one and in two cases two additional SLNs were identified with the ex vivo technique. Twelve percent of tumours were upstaged. CONCLUSION: Ex vivo SLN mapping is as accurate as the in vivo technique in defining SLN and does have the ability to upstage some patients with CCR. The ex vivo technique could be used either as a primary lymphatic mapping procedure or secondarily for failed in vivo attempts at lymphatic mapping.

Assessment of prolonged hospital stay attributable to surgical site infections using appropriateness evaluation protocol.

BACKGROUND: The accepted standard in estimating the stay prolongation attributable to surgical site infections is the matched-cohort study method (MCS), which is associated with selection bias. The Appropriateness Evaluation Protocol (AEP) has been used to estimate stay prolongation attributable to nosocomial infections but has not been validated specifically for surgical site infections. AIM OF THE STUDY: To compare estimates of stay prolongation attributable to surgical site infections after digestive surgery, obtained by AEP and by MCS. METHODS: Sixty-five surgical site infections after digestive tract surgery were analyzed by AEP and MCS. AEP stay prolongation was the number of days judged specifically appropriate for the care of surgical site infections. MCS stay prolongation was the difference of stay duration in surgical site infection cases and two controls matched by age, sex, and diagnosis-related groups. Sensitivity and specificity of AEP, and agreement between both methods, were calculated. RESULTS: The mean AEP stay prolongation was 3.5 days vs 7.2 days for MCS. The sensitivity of AEP was 58% and the specificity was 75%. The agreement between the two methods was poor. CONCLUSION: Surgical site infections after digestive tract surgery increased the hospital stay. Accurate estimations of a prolongation of stay will vary according to the method selected.

Upper jejunal motility after pancreatoduodenectomy according to the type of anastomosis, pancreaticojejunal or pancreaticogastric.

BACKGROUND: The goal of this study was to compare upper jejunal motor patterns after Billroth II pancreatoduodenectomy according to the type of pancreatic anastomosis (pancreaticojejunostomy [PJA] or pancreaticogastrostomy [PGA]) and the presence or absence of postoperative symptoms. STUDY DESIGN: Manometric recordings during fasting and after a 750-kcal meal were performed in the afferent limb in 12 patients (7 PJA, 5 PGA) and in the efferent limb in 15 other patients (7 PJA, 8 PGA) with a postoperative delay of 15+/-6 days and 3.9+/-2.2 months respectively. Patient data were compared to those of 20 healthy controls. RESULTS: During fasting, the 2 main abnormal findings were a higher incidence (p < 0.05) and a slower migration velocity (p < 0.01) of incomplete phase III by comparison with that recorded in controls. No difference for phase III was observed between the 2 surgical procedures regardless of recording site. Trimebutine, 100 mg intravenously, induced a phase III in 89% (24 of 27) of the patients. Delay of motor response varied from 5 to 10 minutes without difference between the recording site; it was less than 2 minutes in 100% of controls. Trimebutine-induced phase III showed similar propagation abnormalities to the spontaneous phase III. Duration of the fed pattern (p < 0.001) and motor index (p < 0.001) were significantly lower than in controls after the meal, in both limbs, whatever the type of anastomosis. Differences between the 2 surgical procedures were a slower migration velocity of phase III (p < 0.01) and a lower postmeal motor index (p < 0.05) in the efferent limb after PJA than after PGA. Nine of 27 patients were symptomatic. In these 9 patients, mean phase III migration velocity was slower (p < 0.001), and mean area under the postprandial curve was higher (p < 0.01) than in asymptomatic patients. Propagated clusters of contractions were only found in symptomatic patients and in the afferent limb. CONCLUSIONS: Pancreatoduodenectomy is associated with significant motor disturbances, mainly slower phase III and a reduced fed pattern, in the upper jejunum, at least during the first 3 postoperative months. Few motor differences were observed between PGA and PJA pancreatic anastomosis. A lesser occurrence of postsurgical motor anomalies does not appear to be an argument for preferring PGA to PJA.

Placebo-controlled clinical trial of mesalazine in the prevention of early endoscopic recurrences after resection for Crohn's disease. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID).

OBJECTIVE: Endoscopic postoperative recurrences occur early after 'curative' surgery for Crohn's disease. Pentasa has been shown to be effective in the maintenance treatment of quiescent Crohn's disease. The aim of this study was to test the efficacy of a 12-week oral intake of Claversal in the prevention of endoscopic recurrences after 'curative' resection for ileal, colonic or ileocolonic Crohn's disease. We conducted a multicentre double-blind controlled trial comparing Claversal (1g tid) with placebo, starting within 15 days after surgery. The macroscopic normality of the two anastomotic segments was assessed at surgery. Patients were clinically and biologically evaluated twice (6-week interval), and colonoscopy was performed at 12 weeks. Endoscopic relapse was defined by any anastomotic ulcerations or stenosis and staged according to a four-grade score. RESULTS: Between May 1989 and May 1991 12 centres included 126 patients, 70 women and 56 men, aged 33 +/- 12 years (range 16-70) in the study. Disease locations were ileal, colonic and ileocolonic in 45, 6 and 49%, respectively. Claversal and placebo groups were similar at inclusion, except for ESR (37 +/- 26 vs. 27 +/- 23 mm/h in the Claversal and placebo groups, respectively; P < 0.05). Nine patients were withdrawn from the study. Adverse reactions occurred only in six patients. Five patients were excluded for protocol violation. Finally, 106 patients could be evaluated at 12 weeks (55 Claversal and 51 placebo). An endoscopic relapse was observed in 50% and 63% of the Claversal and placebo groups, respectively (P = 0.16), with a similar grade distribution. Claversal was well tolerated. CONCLUSIONS: Our study confirms that a large proportion of endoscopic recurrences occur within 3 months of resection in Crohn's disease. There was a slight trend towards greater efficacy of Claversal; it could be worthwhile trying higher dosages and/or 5-ASA compounds with different intestinal release profiles.