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Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial

BACKGROUND Complex perianal fistulas in Crohns disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohns disease. METHODS We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohns disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579. FINDINGS 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2-30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5-31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). INTERPRETATION Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohns disease who did not respond to conventional or biological treatments, or both. FUNDING TiGenix.

Evaluation of the use of posterior tibial nerve stimulation for the treatment of fecal incontinence: preliminary results of a prospective study.

PURPOSE: Neuromodulation therapies have been used with success in patients with fecal incontinence. Intermittent percutaneous tibial nerve stimulation is a new, minimally invasive treatment option for these patients. This study was designed to evaluate the results of intermittent percutaneous tibial nerve stimulation in patients with fecal incontinence. METHODS: Sixteen patients (11 females; mean age, 59 ± 7.9 years) with severe fecal incontinence were treated with percutaneous tibial nerve stimulation. All patients completed a defecation diary, the Wexner Fecal Continence Scale, a fecal incontinence quality-of-life questionnaire, and a visual analog scale before treatment and during each phase of the study. Endoluminal ultrasound and anorectal physiologic studies were also performed in each patient. RESULTS: Continence was improved in 10 of 16 patients after the first phase. Six patients did not continue to the second phase of treatment because of a lack of initial response. During the second phase, 7 of 16 continued to show improvement. After a six-month period without any treatment, 5 of 16 continued to have good continence. Overall, percutaneous tibial nerve stimulation significantly improved fecal continence. The Wexner score improved from a mean of 13.2 ± 4.1 at baseline to 9 ± 5.2 at the end of the first phase (P < 0.0005), to 8 ± 5.7 at the end of the second phase (P = 0.001), and to 9.1 ± 5 after 6 months without treatment (P = 0.001). Significant improvement was observed in three main domains of the fecal incontinence quality-of-life scale: coping/behavior, depression, and embarrassment. Scores on the visual analog scale improved from a mean of 4.6 ± 1.5 at baseline to 7 ± 2.5 at the end of the first phase (P = 0.002) and to 7.2 ± 2.5 after 6 months without treatment (P = 0.001). CONCLUSION: Percutaneous tibial nerve stimulation is a minimally invasive and effective treatment option for patients with fecal incontinence.

Evaluation of a new synthetic plug in the treatment of anal fistulas: results of a pilot study.

BACKGROUND: The treatment of anal fistulas using plugs is a very promising method because of its simplicity and ability to be carried out on an ambulatory basis. If unsuccessful, it does not compromise subsequent alternative surgical techniques and/or products. However, success rates are variable. OBJECTIVE: This pilot study was designed to investigate the safety and effectiveness of a new synthetic plug in the treatment of transsphincteric anal fistulas. DESIGN: This was a prospective observational study. SETTING: Patients were treated at 2 colorectal surgery centers in Spain (Seville and Huelva). INTERVENTIONS: Anal fistulas were treated with a fistula plug made of bioabsorbable polymers (67% polyglycolide, 33% trimethylene carbonate). PATIENTS: Starting in January 2009, consecutive adult patients with transsphincteric anal fistulas were evaluated. MAIN OUTCOME MEASURES: Outcome measures included rates of successful fistula closure, complications, and continence (Jorge-Wexner incontinence score), assessed postoperatively at 1 week and again at 1, 3, 6, and 12 months. Healing was determined by clinical examination by a surgeon blinded for the intervention. RESULTS: A total of 19 patients (18 men, 1 woman) with transsphincteric anal fistulas were included in the study. The median age was 49 (range, 33–65) years. Of these patients, 12 presented with fistula relapse. The median time from onset of symptoms to surgery was 12 (range, 6–120) months. Three patients had previously placed setons. The follow-up duration was 12 months. Relapse occurred in 16 patients (with a perianal abscess in 1), and successful closure was observed in 3 patients (15.8%). LIMITATIONS: The number of patients was small, and time was needed for the learning curve of the technique. CONCLUSIONS: This study indicates that the new synthetic plug is safe, but the fistula closure rate was low. Randomized studies are needed to further determine the role of the bioabsorbable synthetic plug in the management of anal fistulas.

Long-term results change conclusions on BioGlue in the treatment of high transsphincteric anal fistulas.

had had multiple treatments elsewhere; many of these patients were unsuitable for cytoreductive surgery. We showed that major surgery for those in whom CC0/CC1 was not achieved was associated with a poor oncological outcome and high morbidity. Accordingly, we adopted a preoperative selection rather than an “almost all patients” approach. Although we accept that the correlation between preoperative CT imaging and intraoperative disease findings is imperfect, with increasing experience, our multidisciplinary team now readily identifies radiological features—for example, visceral encasement and multiple-level solid disease—that predict a low probability of complete surgical cytoreduction. Similarly to Professor Morris’ team, we too have embraced a variety of techniques to remove gelatinous and solid deposits from small-bowel serosa and mesentery. However, we equally identify patients with extensive solid disease involving the small intestine where complete cytoreduction is unachievable without radical resections and unacceptable concomitant morbidity and poor quality of life. The condition of pseudomyxoma peritonei has conventionally been considered refractory to systemic chemotherapy but our prospective phase II trial of combinational agents was the first to show clinical benefit in one third of the cases, and offers us a further treatment option. In addition, there have been 2 patients in whom downstaging was achieved. The cited M. D. Anderson systemic chemotherapy series was retrospective and comprised heterogeneous pathologies, a skewed range of malignancies (33% signet-ring cell carcinoma), disparate chemotherapy regimens, no toxicity data, and a post hoc subgroup analysis by hyperthermic intraoperative peritoneal chemotherapy status; hence, it is noncontributory to this debate. In reporting a complete cytoreductive surgery rate of 90%, Professor Morris’ series, like others in the literature, is expressing this rate as a proportion of all major surgeries. In our overview, we deliberately used all referred patients as the denominator. As our service has matured over 8 years, the proportion of patients in whom we offer complete cytoreductive surgery has increased but represents a little over a third of all referrals (Table 1). For units starting up this type of program, the important message is to strike a balance between achieving complete cytoreduction and acceptable levels of morbidity and mortality. An “almost all” patients approach may be misleading and is discouraged in our model of centralization.

Robotic-Assisted Total Mesorectal Excision With the Aid of a Single-Port Device

Introduction and indications. Robotic surgery has numerous advantages in rectal cancer surgery. Studies have reported the advantages associated with single-port approaches, such as eliminating the need for additional incisions, as well as the difficulties inherent in this technique. The authors present a hybrid technique that they performed using a robotic total mesorectal excision with the aid of a single port-device. Materials and methods. The authors performed the technique on 2 patients using a single-port device through an umbilical incision and 3 accessory ports for the robotic arms. There was no need to place ports for the assistant’s equipment or for an assistant incision. Results and complications. The operation time was 177.5 minutes, and there were no intraoperative or postoperative complications. Both patients were discharged 7 days after the operation. Conclusions. This technical variation is an additional step forward for oncological surgery with minimal damage to the abdominal wall.

Internal anal sphincter augmentation and substitution

There is an increasing recognition of the importance of internal anal sphincter (IAS) dysfunction presenting as passive faecal incontinence. This problem may manifest after anal sphincterotomy or following the more minimally invasive operations for haemorrhoids, as well as with advancing age. Because of the poor results of IAS plication and the beneficial outcomes with peri-urethral bulking agents in urology, these materials have been developed for use in IAS dysfunction. This review outlines the basic purported mechanisms of action, defining the materials in clinical use, their methods of deployment, complications and reported outcomes. There is still much that is unknown concerning the ideal agent or the volume and the technique of deployment, which will only be answered by powerful, prospective, randomized, controlled trials. The specific role of autologous stem cells designed to regenerate the sphincters in cases of functional impairment or muscle loss is yet to be seen.

Adenosis tumour of anogenital mammary-like glands

Dear Editor: Anogenital mammary-like glands, although known to exist (as ectopic breast tissue) as early as 1872, have recently been thoroughly studied. They have been suggested to be the possible origin for various neoplastic (benign and malignant) and reactive conditions that show a striking homology with lesions in the breast. The term “adenosis tumour” was coined for a clinically detectable mammary tumour in which several benign changes, often occurring as isolated lesions of the breast, are seen in combinations. We describe a lesion that occurred in the anogenital area of a woman and apparently arose in anogenital mammarylike glands. A 64-year-old woman presented with a solitary asymptomatic lesion located in the perianal area. She was uncertain about the duration of the lesion. Her past medical history was unremarkable. Clinical examination revealed a 1.7-cm oval nodule. Rectoscopy revealed an internal haemorrhoid. The lesion was surgically removed. The patient showed no recurrence 7 months after the surgery. Histologic examination revealed a well-delimited but not encapsulated nodule with little surrounding connective tissue composed of fibrous stroma and glands and ducts, many cystic or with cellular proliferation, reminiscent of mammary glands; papillary areas and apocrine metaplasia could also be seen. An immunohistochemical study was performed, showing a myoepithelial (actin-positive) and a cytokeratin 7+/20− epithelial component with marked EMA expression but not of CEA. Approximately 15% of cells expressed oestrogen and/or progesterone receptor. Anogenital “sweat glands”, recently termed as anogenital mammary-like glands, are a newly recognised variant of cutaneous adnexal glands and may play an important role in a group of neoplastic disorders of the anogenital region in both women and men. These glands appear to be eccrine glands that transform fully or partially into apocrine glands with the capacity to form breast lobules and histologic, biochemical and ultrastructural features that fall somewhere in between conventional sweat glands and breast tissue. The secretory epithelium of mammary-like glands is characteristically tall columnar with snouts, can express both oestrogen and progesterone receptors and shows drastic periodic alterations. It is important for everybody to be familiar with mammarylike glands because they can give rise not only to tumour adenosis, but also to hidradenoma papilliferum, extramammary Paget’s disease, fibroadenoma, phyllodes tumour, anogenital mammary type sclerosing adenosis, lactating adenoma, adenocarcinomas, stromal hyperplasia and lobular hyperplasia. Adenosis originating from mammary-like anogenital glands is rare; to date, only eight cases have been documented in the literature, including the case described herein. Adenosis tumour is defined as clinically recognisable lesions that histologically primarily consist of adenosis, but also exhibits various combinations of diverse epithelial changes seen in other benign breast diseases. Int J Colorectal Dis (2008) 32:223–224 DOI 10.1007/s00384-007-0323-x

Calcium alginate as a rectal bulking agent. Experimental pilot study to determine its migratory trend and locoregional reaction

Dear Editor: Faecal incontinence affects an estimated 2 % of the population. Most patients can be treated either conservatively or by surgical repair if there is a physical disruption of the anal sphincter. A minimally invasive approach involving the injection of a bulking agent either around the IAS or into a defect in the IAS is a simple option for the treatment of this condition, and various materials have been tested to that end. Ideally, a filling material should be easy to inject, biocompatible, non-carcinogenic, non-immunogenic, and should induce minimal inflammatory and fibrotic responses. The agent particles should be big enough to avoid migration away from the injection site (diameter >80 μm), but they should be durable enough to last for a sufficient length of time. Several newly applied materials consisting of natural or synthetic polymers appear to be as efficacious as the therapies currently employed, but extensive long-term data are not yet available. Alginates are a family of polysaccharides found in brown seaweed. Broadly considered to be biocompatible, they have been used extensively in the food, pharmaceutical, and medical device industries. Previous research in animals has shown encouraging results regarding the use of an injectable alginate hydrogel as a bulking agent. We have performed a pilot study to evaluate the locoregional behaviour andmigration after local rectal submucosal injection of an alginate hydrogel.

Aproximación al estado actual de la proctología en Andalucía: resultados de una encuesta comunitaria

OBJECTIVE: Proctology has acquired such complexity that it requires a specific qualification, as well as the creation of specialized groups. In Andalusia there are proctologists throughout the public health system. Measurement of the quality of the distinct processes is essential. The aim of the present study was to determine the resources available, as well as to identify the management of these patients, with a view to identifying areas requiring improvement. MATERIALS AND METHOD: A descriptive, multicenter, cross sectional study of the current situation of proctology in general surgery services in 25 hospitals in Andalusia (20 public and 5 private) was performed. A survey was used to identify the general characteristics of the hospital, the tests available, and the treatments used. RESULTS: A total of 65.38% of the hospitals have a coloproctology unit, while a drop-in outpatient clinic is available in only 38.46%. Manometry and anal endosonography are available in 50% and 58%, respectively. Treatment of hemorrhoids is predominantly hemorrhoidectomy (92.30%). Medical treatment and sphincterotomy are the most widely used treatments for anal fissure, and anal dilation is still performed in 30.76%. Seton is used in 92.30%, as well as fistulotomy (88.46%), to treat fistula. The most frequent treatment of sinus is en-bloc resection and primary closure (54.16%). Between 30% and 44% report little experience of pelvic floor disorders. CONCLUSION: Although there is a willingness to achieve progress and reach an adequate scientific level, a multitude of obsolete practices should be corrected. Tools such as scientific evidence, information management and evaluation by means of comparison with standards should be diligently included in our clinical practice.

Utilidad de la ecografía dinámica tridimensional en el estudio del suelo pélvico

INTRODUCTION Dynamic endoanal ultrasound has emerged in recent years as a test that could replace the now existing tests in the diagnosis of pelvic floor disorders. The aim of this paper is to determine the usefulness of echodefecography in the diagnosis and evaluation of patients with symptoms of anorrectal obstruction, and show the results obtained after its implementation in a pelvic floor unit, as a complementary tool that could replace conventional defecography. METHODS In this retrospective study we analyzed 66 patients with a mean age of 55 years (19-83), 61 women (92%). All dynamic ultrasound was performed in 3 dimensions and was correlated with symptoms and physical findings in the consultation. A descriptive and inferential study was performed to find a kappa correlation between physical examination and echodefecography. RESULTS The reasons for consultation were: Anorrectal obstruction syndrome 36 patients (54.5%), pelvic organ prolapse 27 patients (40.9%), and anorrectal obstruction syndrome along with pelvic organ prolapse 3 patients (4.5%). The correlation of the 2 groups indicated that echodefecography diagnosed more patients with grade III rectocele, enteroceles, and anismus than the combination of scan-ultrasound-manometry-proctoscopy (Kappa 0.26, 0.38 and 0.21, 95% CI: from 0,07 to 1.00, 0.15 to 1.00 and from 0.12 to 1.00, respectively) (P<.001). Conversely, echodefecography diagnosed less perineal descense (Kappa 0.28, 95% CI: 0.12 to 1.00). CONCLUSIONS Dynamic anal ultrasonography may have a role as a complementary test in patients with pelvic floor disorders, achieving diagnoses that would go undetected by inspection, physical examination and manometry.